Fluvastatin sodium crystal forms, processes for preparing them, compositions containing them and methods of using them

ABSTRACT

Provided are crystalline forms of fluvastatin sodium and processes for their preparation.

PRIORITY

This application is a divisional application of allowed U.S. applicationSer. No. 10/872,089; which claims the benefit of U.S. ProvisionalApplication Ser. Nos. 60/479,182 filed Jun. 18, 2003; 60/483,099 filedJun. 30, 2003; 60/485,748 filed Jul. 10, 2003; 60/493,793 filed Aug. 11,2003; 60/507,954 filed Oct. 3, 2003 and 60/545,466 filed Feb. 19, 2004,all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the antihypercholesterolemia andantilipidemia agent fluvastatin and, more particularly, to the solidstate properties of its monosodium salt.

BACKGROUND OF THE INVENTION

Complications of cardiovascular disease, such as myocardial infarction,stroke, and peripheral vascular disease account for half of the deathsin the United States. A high level of low density lipoprotein (LDL) inthe bloodstream has been linked to the formation of coronary lesionswhich obstruct the flow of blood and can rupture and promote thrombosis.Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9thed. 1996). Reducing plasma LDL levels has been shown to reduce the riskof clinical events in patients with cardiovascular disease and inpatients who are free of cardiovascular disease but who havehypercholesterolemia. Scandinavian Simvastatin Survival Study Group,1994; Lipid Research Clinics Program, 1984a, 1984b.

Statin drugs are currently the most therapeutically effective drugsavailable for reducing the level of LDL in the blood stream of a patientat risk for cardiovascular disease. This class of drugs includes, interalia, compactin, lovastatin, simvastatin, pravastatin and fluvastatin.The mechanism of action of statin drugs has been elucidated in somedetail. They disrupt the synthesis of cholesterol and other sterols inthe liver by competitively inhibiting the3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoAreductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA tomevalonate, which is the rate determining step in the biosynthesis ofcholesterol. Consequently, its inhibition leads to a reduction in therate of formation of cholesterol in the liver.

[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoicacid is a statin drug. It is known by the trivial name fluvastatin andhas the molecular formula (I):

depicted in free acid form.

Fluvastatin is commercially available under the trade name Lescol®.Fluvastatin is supplied as a monosodium salt in capsules containing theequivalent of 20 and 40 mg of fluvastatin and in extended-releasetablets containing the equivalent of 80 mg of fluvastatin. Fluvastatinand its sodium salt are described in U.S. Pat. No. 4,739,073. In Example6(a) of the '073 patent, a methyl ester precursor of (±) fluvastatin washydrolyzed with sodium hydroxide in methanol, which yielded, afterevaporation of the methanol, crude fluvastatin sodium. In Example 6(b),the fluvastatin methyl ester was hydrolyzed with sodium hydroxide inethanol. After evaporation of the ethanol, the residue was taken up inwater and lyophilized. The lyophilized product had a melting point rangeof 194EC-197EC. In Example 8, the sodium salt was prepared by ringopening of fluvastatin lactone with sodium hydroxide in ethanol asdescribed in Example 6(b). The product of Example 8 produced an infraredspectrum in a KBr pellet with bands at: 3413, 2978, 2936, 1572 and 1216cm⁻¹.

According to U.S. Pat. No. 6,124,340, lyophilization of fluvastatinsodium as was performed in Examples 6(b) and 8 of the '073 patent yieldssolid fluvastatin sodium as a mixture of a crystalline form, designatedas Form A, and amorphous material. The '340 patent sets forth thespectroscopic properties of another crystal form of fluvastatin sodiumwhich is said to have low hygroscopicity and photostability. This otherform is called Form B in the '340 patent. It is characterized by aninfrared spectrum with bands at 3343, 2995, 1587, 1536, 1386, 1337, 1042and 1014 cm⁻¹ and by the following powder X-ray diffraction peakpositions and intensities.

E22 d (Δ) I/I_(O) (%) 4.063 21.728 100 11.056 7.996 2.9 11.328 7.805 5.512.210 7.243 45.2 12.965 6.823 34.6 14.925 5.931 9.3 15.277 5.795 4.515.750 5.622 18.5 16.350 5.417 10.6 17.760 4.990 17.6 18.320 4.839 14.318.875 4.698 11.3 19.396 4.573 7.0 19.701 4.503 13.4 20.395 4.351 13.521.329 4.163 8.5 21.785 4.076 15.9 22.610 3.929 7.5 23.868 3.725 5.424.281 3.663 3.6 24.463 3.636 3.6 25.446 3.498 5.6 25.655 3.470 3.626.357 3.379 3.3 27.040 3.295 2.8 28.747 3.103 3.4 29.940 2.982 2.832.165 2.781 1.6 35.173 2.549 1.0 37.131 2.419 1.3

Fluvastatin sodium Form A is said to have the following powder X-raydiffraction peak positions and intensities.

E22 d (Δ) I/I_(O) (%) 3.965 22.265 100 7.936 11.131 0.9 10.554 8.375 1.710.645 8.304 1.5 11.931 7.412 44.5 12.215 7.240 14.5 14.496 6.106 1.114.812 5.976 0.8 15.916 5.564 0.3 17.769 4.988 3.2 18.640 4.756 5.319.856 4.468 5.8 20.518 4.325 2.9 20.908 4.245 1.2 21.389 4.151 1.321.722 4.088 1.1 22.675 3.918 0.8 24.089 3.691 1.0 24.533 3.626 0.526.519 3.358 0.2 27.973 3.187 0.9 28.861 3.091

U.S. Patent Application Publication No. 2003/0032666 reports theexistence of four crystal forms of fluvastatin monosodium called FormsC, D, E and F. The water content of the forms ranges between 3 and 32%.The new crystal forms of fluvastatin sodium were obtained by storing thesamples under atmospheres ranging between 20 and 90% relative humidity.

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form C possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Δ) Intensity 23.8 (vs) 11.8 (w) 7.8 (vs) 7.6 (vw) 7.4 (vw) 6.4 (vw)6.1 (vw) 5.90 (w) 5.00 (vw) 4.88 (w) 4.73 (m) 4.56 (w) 4.40 (vw) 4.12(vw) 4.03 (vw) 3.96 (vw) 3.50 (vw) 3.36 (vw) 2.93 (vw)wherein (vs)=very strong intensity; (s)=strong intensity; (m)=mediumintensity; (w)=weak intensity; and (vw)=very weak intensity.

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form D possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Δ) Intensity 24.6 (vs) 12.5 (w) 8.3 (vs) 7.4 (vw) 6.2 (m) 4.97 (w)4.85 (vw) 4.52 (vw) 4.40 (vw) 4.14 (vw) 3.96 (vw) 3.41 (vw) 3.10 (vw)

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form E possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Δ) Intensity 27.6 (m) 13.9 (vw) 9.2 (m) 8.5 (vw) 8.1 (vw) 7.4 (vw)6.9 (s) 6.1 (vw) 4.98 (m) 4.77 (m) 4.63 (m) 4.15 (w) 4.03 (w) 3.97 (vw)3.52 (vw) 3.33 (vw) 3.08 (vw) 2.99 (vw)

According to the '666 publication, the PXRD pattern of fluvastatinsodium Form F possesses characteristic peaks at the following d-valuesand qualitative intensities:

d (Δ) Intensity 29.6 (w) 14.8 (vw) 9.9 (w) 8.6 (vw) 8.3 (vw) 7.4 (s) 6.6(vw) 6.2 (vw) 5.93 (w) 5.03 (m) 4.94 (m) 4.35 (vw) 4.23 (w) 3.98 (vw)3.54 (vw) 2.98 (vw)

It also deserves mention that International Publication No. WO 02/36563discloses crystal forms of enantiomerically pure [3R,5S] and [3S,5R]fluvastatin sodium.

The present invention also relates to fluvastatin sodium and theproperties that it can exhibit in the condensed phase. The occurrence ofdifferent crystal forms (polymorphism) is a property of some moleculesand molecular complexes. A single molecule, like the fluvastatin informula (I) or a salt complex like fluvastatin sodium, may give rise toa variety of solids having distinct physical properties like meltingpoint, X-ray diffraction pattern, infrared absorption fingerprint andNMR spectrum. The crystalline form may give rise to thermal behaviordifferent from that of the amorphous material or another crystallineform. Thermal behavior is measured in the laboratory by such techniquesas capillary melting point, thermogravimetric analysis (“TGA”) anddifferential scanning calorimetry (“DSC”) and can be used to distinguishsome polymorphic forms from others. The differences in the physicalproperties of different crystalline forms result from the orientationand intermolecular interactions of adjacent molecules (complexes) in thebulk solid. Accordingly, polymorphs are distinct solids sharing the samemolecular formula yet having distinct advantageous and/ordisadvantageous physical properties compared to other forms in thepolymorph family. These properties can be influenced by controlling theconditions under which the salt is obtained in solid form.

Exemplary solid state physical properties include the flowability of themilled solid. Flowability affects the ease with which the material ishandled during processing into a pharmaceutical product. When particlesof the powdered compound do not flow past each other easily, aformulation specialist must take that fact into account in developing atablet or capsule formulation, which may necessitate the use of glidantssuch as colloidal silicon dioxide, talc, starch or tribasic calciumphosphate.

One of the most important physical properties of pharmaceuticalpolymorphs is their solubility in aqueous solution, particularly theirsolubility in the gastric juices of a patient. For example, whereabsorption through the gastrointestinal tract is slow, it is oftendesirable for a drug that is unstable to conditions in the patient'sstomach or intestine to dissolve slowly so that it does not accumulatein a deleterious environment. On the other hand, the method is notadvantageous where the effectiveness of a drug correlates with peakbloodstream levels of the drug, as in the case of statin drugs. With astatin drug, provided the drug is rapidly absorbed by the GI system, amore rapidly dissolving form is likely to exhibit increasedeffectiveness over a comparable amount of a more slowly dissolving form.

It is often the case that the most rapidly dissolving solid state of acompound is amorphous. Amorphous forms are often less stable thancrystalline forms because they do not have many of the stabilizingintermolecular interactions that are present in crystalline forms. Withan amorphous form, therefore, stabilizing intermolecular interactions donot have to be broken when the compound goes into solution, and so thedissolution rate is not retarded. Although they are more rapidlydissolving than crystalline forms, amorphous forms of a compound canhave disadvantages. A compound, when it is in an amorphous state, isfrequently more hygroscopic than a crystalline form of the same compound(although exceptions abound, such as when the crystal has wide channelsthat allow water to enter and leave the crystal in response to changesin moisture density outside the crystal). Water has been implicated indrug stability problems. For instance the decomposition of aspirin whichleads to the characteristic smell of vinegar when an old bottle ofaspirin is opened is a hydrolysis reaction catalyzed by water. It isthus prudent when selecting a solid state form of a compound that is tobe used as a drug, and possibly stored for a long time between packagingand use, to select a form that has low permeability to water. In thecase of fluvastatin monosodium, a crystalline form designated Form B hasalready been discovered that is purportedly less hygroscopic than thepartially crystalline/partially amorphous form of the salt that isobtained by following procedures in U.S. Pat. No. 4,739,073.

Although six distinct crystalline forms of racemic fluvastatin sodiumhave been reported to date, and at least one of them is purported to beless hygroscopic that the solid state form originally reported by thediscovers of the compound, the discovery of yet other crystalline formsof fluvastatin sodium is desirable. The discovery of new crystallineforms and solvates of a pharmaceutically useful compound provides a newopportunity to improve the performance characteristics of apharmaceutical product by enlarging the repertoire of materials that aformulation scientist has available for designing. For example, newcrystalline forms can be used to design a pharmaceutical dosage form ofa drug with low hygroscopicity, a targeted release profile, consistentdosing (enabled by good flow of the tableting composition into thetableting die), or other desired characteristic. New polymorphic formsand solvates of fluvastatin have now been discovered.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a powder X-ray diffractogram of fluvastatin sodium FormI.

FIG. 2 depicts a powder X-ray diffractogram of fluvastatin sodium FormII.

FIG. 3 depicts a powder X-ray diffractogram of fluvastatin sodium FormIII.

FIG. 4 depicts a powder X-ray diffractogram of fluvastatin sodium FormIV.

FIG. 5 depicts a DSC thermogram of fluvastatin sodium Form IV.

FIG. 6 depicts an IR spectrum of fluvastatin sodium Form IV scanned from4000 to 400 cm⁻¹, while FIG. 6 a expands the 4000-1500 cm⁻¹ region ofthe spectrum and FIG. 6 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 7 depicts a powder X-ray diffractogram of fluvastatin sodium FormIV-1.

FIG. 8 depicts a DSC thermogram of fluvastatin sodium Form IV-1.

FIG. 9 depicts an IR spectrum of fluvastatin sodium Form IV-1 scannedfrom 4000 to 400 cm⁻¹, while FIG. 9 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 9 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 10 depicts a powder X-ray diffractogram of fluvastatin sodium FormV.

FIG. 11 depicts a powder X-ray diffractogram of fluvastatin sodium FormVI.

FIG. 12 depicts a DSC thermogram of fluvastatin sodium Form VI.

FIG. 13 depicts an IR spectrum of fluvastatin sodium Form VI scannedfrom 4000 to 400 cm⁻, while FIG. 13 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 13 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 14 depicts a powder X-ray diffractogram of fluvastatin sodium FormVII.

FIG. 15 depicts a DSC thermogram of fluvastatin sodium Form VII.

FIG. 16 depicts an IR spectrum of fluvastatin sodium Form VII scannedfrom 4000 to 400 cm⁻¹, while FIG. 16 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 16 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 17 depicts a powder X-ray diffractogram of fluvastatin sodium FormIX.

FIG. 18 depicts a powder X-ray diffractogram of fluvastatin sodium FormIX-1.

FIG. 19 depicts a powder X-ray diffractogram of fluvastatin sodium FormXI.

FIG. 20 depicts a DSC thermogram of fluvastatin sodium Form XI.

FIG. 21 depicts an IR spectrum of fluvastatin sodium Form XI scannedfrom 4000 to 400 cm⁻¹, while FIG. 21 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 21 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 22 depicts a powder X-ray diffractogram of fluvastatin sodium FormXI-2.

FIG. 23 depicts a DSC thermogram of fluvastatin sodium Form XI-2.

FIG. 24 depicts an IR spectrum of fluvastatin sodium Form XI-2 scannedfrom 4000 to 400 cm⁻¹, while FIG. 24 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 24 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 25 depicts a powder X-ray diffractogram of fluvastatin sodium FormXII.

FIG. 26 depicts a powder X-ray diffractogram of fluvastatin sodium FormXIII.

FIG. 30 depicts a powder X-ray diffractogram of fluvastatin sodium FormXV.

FIG. 31 depicts a powder X-ray diffractogram of fluvastatin sodium FormXVI.

FIG. 32 depicts a DSC thermogram of fluvastatin sodium Form XVI.

FIG. 33 depicts an IR spectrum of fluvastatin sodium Form XVI scannedfrom 4000 to 400 cm⁻¹, while FIG. 33 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 33 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 34 depicts a powder X-ray diffractogram of fluvastatin sodium FormXVII.

FIG. 35 depicts a DSC thermogram of fluvastatin sodium Form XVII.

FIG. 36 depicts a powder X-ray diffractogram of fluvastatin sodium FormXVIII.

FIG. 37 depicts a DSC thermogram of fluvastatin sodium Form XVIII.

FIG. 38 depicts an IR spectrum of fluvastatin sodium Form XVIII scannedfrom 4000 to 400 cm⁻¹, while FIG. 38 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 38 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 39 depicts a powder X-ray diffractogram of fluvastatin sodium FormXIX.

FIG. 40 depicts a DSC thermogram of fluvastatin sodium Form XIX.

FIG. 41 depicts an IR spectrum of fluvastatin sodium Form XIX scannedfrom 4000 to 400 cm⁻¹, while FIG. 41 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 41 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 42 depicts a powder X-ray diffractogram of fluvastatin sodium FormXIX-1.

FIG. 43 depicts a powder X-ray diffractogram of fluvastatin sodium FormXX.

FIG. 44 depicts a DSC thermogram of fluvastatin sodium Form XX.

FIG. 45 depicts an IR spectrum of fluvastatin sodium Form XX scannedfrom 4000 to 400 cm⁻¹, while FIG. 45 a expands the 4000-1500 cm⁻¹ regionof the spectrum and FIG. 45 b expands the 1500-400 cm⁻¹ region of thespectrum.

FIG. 46 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXII.

FIG. 47 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXIII.

FIG. 48 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXIV.

FIG. 49 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXVI.

FIG. 50 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXVII.

FIG. 51 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXIX.

FIG. 52 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXX.

FIG. 53 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXI.

FIG. 54 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXIII.

FIG. 55 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXIV.

FIG. 56 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXV.

FIG. 57 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXVI.

FIG. 58 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXVII.

FIG. 59 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXVIII.

FIG. 60 depicts a powder X-ray diffractogram of fluvastatin sodium FormXXXIX.

FIG. 61 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLI.

FIG. 62 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLII

FIG. 63 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLIII.

FIG. 64 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLIV.

FIG. 65 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLV.

FIG. 66 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLVI.

FIG. 67 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLVII.

FIG. 68 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLVIII.

FIG. 69 depicts a powder X-ray diffractogram of fluvastatin sodium FormXLIX.

FIG. 70 depicts a powder X-ray diffractogram of fluvastatin sodium FormL.

FIG. 71 depicts a powder X-ray diffractogram of fluvastatin sodium FormLI.

FIG. 72 depicts a powder X-ray diffractogram of fluvastatin sodium FormLIII.

FIG. 73 depicts a powder X-ray diffractogram of fluvastatin sodium FormLIV.

FIG. 74 depicts a powder X-ray diffractogram of fluvastatin sodium FormLV.

FIG. 75 depicts a powder X-ray diffractogram of fluvastatin sodium FormLVI.

FIG. 76 depicts a powder X-ray diffractogram of fluvastatin sodium FormLVII

FIG. 77 depicts a powder X-ray diffractogram of fluvastatin sodium FormLVIII.

FIG. 78 depicts a powder X-ray diffractogram of fluvastatin sodium FormLX.

FIG. 79 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXIV.

FIG. 80 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXV.

FIG. 81 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXVI.

FIG. 82 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXVII.

FIG. 83 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXVIII.

FIG. 84 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXIX.

FIG. 85 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXX.

FIG. 86 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXI.

FIG. 87 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXII.

FIG. 89 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXIV.

FIG. 90 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXV.

FIG. 91 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXVI.

FIG. 92 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXVII.

FIG. 93 depicts a powder X-ray diffractogram of fluvastatin sodium FormLXXVIII.

FIG. 97 depicts a powder X-ray diffractogram of fluvastatin sodium FormXC.

FIG. 98 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCI.

FIG. 99 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCII.

FIG. 100 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCIII.

FIG. 101 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCIV.

FIG. 102 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCV.

FIG. 103 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCVI.

FIG. 104 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCVII.

FIG. 105 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCVIII.

FIG. 106 depicts a powder X-ray diffractogram of fluvastatin sodium FormXCIX.

FIG. 107 depicts a powder X-ray diffractogram of fluvastatin sodium FormC.

FIG. 108 depicts a powder X-ray diffractogram of fluvastatin sodium FormCI.

FIG. 109 depicts a powder X-ray diffractogram of fluvastatin sodium FormCII.

FIG. 110 depicts a powder X-ray diffractogram of fluvastatin sodium FormCIII.

FIG. 111 depicts a powder X-ray diffractogram of fluvastatin sodium FormCIV.

FIG. 112 depicts a powder X-ray diffractogram of fluvastatin sodium FormCV.

SUMMARY OF THE INVENTION

In one aspect the present invention provides various polymorphic formsof fluvastatin sodium. The polymorphic forms are identified inter aliaby various characteristic PXRD peaks.

In another aspect, the present invention provides processes forpreparation of these polymorphic forms. These polymorphic forms areprepared by various processes as set out in the examples and theDetailed Description of the Invention.

In another aspect, the present invention provides for pharmaceuticalformulations prepared from such polymorphic forms.

In another aspect, the present invention provides for treatment ofhypercholesterolemia or hyperlipidemia in a mammal by administering thepharmaceutical compositions to the mammal.

These polymorphic forms are useful inter alia for preparation ofpharmaceutical compositions of fluvastatin sodium, purification offluvastatin since many are of high crystallinity, and/or as startingmaterial for preparation of other polymorphic forms of fluvastatinsodium.

The claims further provide a summary of the present invention. Eventhough the claims are not in multiple dependent format, the summary ofthe invention includes processes as set out in the claims dependent onall possible product claims, i.e., for the same polymorph, and all otherpossible process claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein, a lower alkyl group refers to a C₁ to C₄ alkyl group.

The present invention provides novel crystal forms of[R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoicacid monosodium (fluvastatin sodium). The novel crystalline forms offluvastatin sodium have been designated Forms I, II, III, IV, IV-1, V,VI, VII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1,XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV,XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI,XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV,LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI,LXXVII, LXXVIII, XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII,XCIX, C, CI, CII, CIII, CIV, and CV. In so doing we have opted to useRoman numerals as labels for the crystals instead of the Romanalphabetical labels used by others working in the field to label othercrystalline forms of fluvastatin sodium.

Fluvastatin sodium crystal forms XIV, LXXIII, LXXIX, LXXX and LXXXVIIappear in the priority applications of the present invention, and arepresent in another application filed on the same day.

Whether the two enantiomers of [R*,S*-(E)]-(±) fluvastatin sodiumco-crystallize in a single unit cell or whether they crystallize inseparate unit cells that are mirror images of each other has yet to bedetermined for all of the new crystals forms. Accordingly, the crystalforms of this invention are considered to include crystals that exhibitsubstantially the same PXRD patterns as those depicted in the figureswhether they are prepared starting from pure or enriched [R*,S*-(E)]-(+)and [R*,S*-(E)]-(−) fluvastatin sodium or racemic fluvastatin sodium.

Many of the novel forms can be obtained by crystallization methods andare stable under normal humidity conditions. Those skilled in the art,after reading this disclosure will appreciate that some of thecrystallization processes by which the new forms can be made sharecertain traits. Generally speaking, in those processes fluvastatinsodium is dissolved in a solvent, the selection of which is taught withreference to each particular crystalline form in the sections of thisdisclosure that follow. While the solution of fluvastatin sodium in thesolvent is refluxing, a selected anti-solvent (the selection of whichalso is taught below) is added to the solution to induce precipitationof fluvastatin sodium in the crystalline form desired. The anti-solventaddition and precipitation can be performed, and preferably areperformed, at elevated temperature. Additional precipitation, of course,will occur in many cases during subsequent cooling of the mixture. Itwill also be seen that in other processes heating of the solvent is notpreferred.

By the crystallization processes of this invention, each of the novelcrystal forms of fluvastatin sodium is obtained substantially free fromother crystal forms, which means less than 5% of any other crystal formas measured by X-ray powder diffraction. Although these processes havebeen found to yield the novel crystal forms, and yield them in highpurity, other processes that produce the crystal forms of this inventionin either greater or lesser purity may yet be found.

The yields of the various processes for preparing the new fluvastatinsodium crystal forms vary greatly depending upon the form desired. Asthose skilled in the art will appreciate, a low yield of the desiredcrystal form does not necessarily mean that precious unconvertedstarting material is lost. It, or another crystalline or amorphous formof fluvastatin sodium or fluvastatin free acid or lactone can berecovered from the separated solvent or diluent, such as by evaporatingthe separated diluent or solvent used in the process to leave a residuecontaining fluvastatin.

Some of the new forms of fluvastatin sodium are hydrated. The level ofwater in fluvastatin sodium is measured by Karl Fisher using methodsknown in the art. Some of the new crystal forms of fluvastatin sodiumcontain residual solvent in addition to water, which is seen by the factthat the TGA weight loss value is significantly larger than the KarlFisher value. Some of the solvated crystal forms contain only smallquantities of residual solvent. In this latter group fluvastatin sodiumcan be found in the following hydrated states: hemihydrate (watercontent about 2%); monohydrate (water content about 3-4%); sesquihydrate(water content about 5-6%); dihydrate (water content about 7-8%);hemipentahydrate (water content about 9-10%); trihydrate (water contentabout 11-13%); tetrahydrate (water content about 14-16%); pentahydrate(water content 17-18%); hexahydrate (water content about 19-20%);8-hydrate (water content about 25%); 9-hydrate (water content about27-28%).

Fluvastatin is a known compound that can be purchased from commercialsources or synthesized by known processes such as the process disclosedin U.S. Pat. No. 4,739,073, which is incorporated herein by reference inits entirety. In particular, U.S. Pat. No. 4,739,073 is incorporatedherein for its disclosure of how to prepare fluvastatin and fluvastatinsodium. In the processes of this invention that use fluvastatin sodiumas a starting material, fluvastatin sodium Form B is the preferredstarting material unless otherwise indicated.

As used in this disclosure, the term “elevated temperature” means atemperature above ambient temperature or above about 25EC. Preferredelevated temperatures are 50EC and above and especially preferredelevated temperatures, when used in reference to contacting withparticular liquids, are the boiling points of such liquids.

The term “anti-solvent” means a liquid that, when added to a solution offluvastatin sodium in a solvent, induces precipitation of fluvastatinsodium. Precipitation of fluvastatin sodium is induced by theanti-solvent when addition of the anti-solvent causes fluvastatin sodiumto precipitate from the solution more rapidly or to a greater extentthan fluvastatin sodium precipitates from a solution containing an equalconcentration of fluvastatin in the same solvent when the solution ismaintained under the same conditions for the same period of time butwithout adding the anti-solvent. Precipitation can be perceived visuallyas a clouding of the solution or formation of distinct particles offluvastatin sodium suspended in or on the surface of the solution orcollected on the walls or at the bottom of the vessel containing thesolution.

Fluvastatin Sodium Crystal Form I

Fluvastatin sodium Form I produces a PXRD diffractogram withcharacteristic peaks at 3.7, 11.3, 13.1, 17.9, 18.4 and 21.8 degreestwo-theta (FIG. 1).

Fluvastatin sodium Form I can be prepared directly from a lower alkylester of fluvastatin such as fluvastatin methyl ester. The ester isdissolved in a solution of about one molar equivalent of sodium in asolvent selected from acetone and acetonitrile. The sodium can beconveniently provided by dissolving the appropriate quantity of sodiumhydroxide pellets in water, acetone or acetonitrile, while exercisingcaution since the dissolution in water is highly exothermic. Fluvastatinsodium Form I forms as a precipitate in the solvent and can beconventionally separated therefrom by a known method of isolation suchas filtering, decanting, centrifuging and the like, preferably filteringunder a nitrogen stream.

Form I can also be prepared by crystallization from acetone or a mixtureof butan-2-ol and water, with a 10:1 butan-2-ol:water mixture beingespecially preferred. Preferably Form B is dissolved in the solvent atthe solvent's reflux temperature a reflux temperature by adding the FormB to the refluxing solvent.

According to a preferred procedure about 0.05:1 (w/v) of Form B is addedto refluxing acetone. If Form B does not completely dissolve after areasonable period of time, the hot solution may be filtered to removeany undissolved particles. Next, about 1:3 (v/v) of MTBE is added to thesolution. The mixture is then allowed to cool. If Form I does notprecipitate after cooling to ambient temperature, then an additionalquantity of MTBE can be added to the solution and it can be partiallyconcentrated on a rotary evaporator to induce precipitation. The productis then isolated using conventional methods.

According to another preferred procedure, about 1:20 (w/v) of Form B isadded to a refluxing 10:1 butan-2-ol:water mixture. After dissolution iscomplete, the mixture is cooled or allowed to cool to induceprecipitation after which Form I is isolated conventionally.

Fluvastatin Sodium Crystal Form II

Fluvastatin sodium Form II produces a PXRD diffractogram (FIG. 2) with acharacteristic peak at 3.6±0.2 degrees two-theta and other peaks at 5.4,5.7, 10.7 and 20.3±0.2 degrees two-theta.

Form II can be prepared from either fluvastatin sodium such as Form B oramorphous fluvastatin. Starting from Form B, the starting material istaken up in refluxing butan-1-ol. The solution is then cooled or allowedto cool to ambient temperature and is allowed to stand without seedinguntil a precipitate is observed. Starting with amorphous fluvastatinsodium, about 1:21 (w/v) of the starting material is suspended inrefluxing propan-2-ol. The suspension is then allowed to cool and standuntil precipitation occurs.

Following either procedure, the precipitate is separated from thediluent by conventional techniques such as filtering, decanting,centrifuging and the like. Drying may be carried out at 50EC in a vacuumoven.

Fluvastatin Sodium Crystal Form III

Fluvastatin sodium Form III produces a PXRD diffractogram withcharacteristic peaks at 3.5, 9.5, 10.1, 10.9 and 20.1 degrees two-theta(FIG. 2).

Like Form II, Form III can be prepared from a form of fluvastatin sodiumsuch as either Form B or amorphous fluvastatin sodium. In addition, itcan be prepared from fluvastatin sodium Form XIV.

Starting from Form B, the starting material is dissolved in a solventselected from the group consisting of butan-1-ol, ethyl acetate and THF.Form B is preferably dissolved at the reflux temperature of the solvent.If the Form B does not completely dissolve, the hot solution can befiltered to obtain a clear filtrate. While at reflux temperature, ananti-solvent selected from the group consisting of MTBE, hexanes andcyclohexane, is slowly added to the solution (dropwise addition on thebench scale). Addition of the anti-solvent may induce precipitation atelevated temperature. If it does not, Form III should precipitate uponcooling the solution to ambient temperature.

Starting from amorphous fluvastatin sodium, about 1:6 (w/v) of thestarting material is dissolved in refluxing ethanol. While the solutionis refluxing, Form III should be seen to come out of solution. If itdoes not precipitate within about an hour, the solution can be cooled toambient temperature, which should induce precipitation of Form III.

Starting from fluvastatin sodium Form XIV, about 1:7 (w/v) of thestarting material is suspended in refluxing ethanol for a period of timesufficient to effect the conversion to Form III, which may take severalhours or days. Thereafter the suspension is cooled to ambienttemperature and the precipitate is isolated.

In each of these procedures for making fluvastatin sodium Form III, theproduct may be separated from the diluent by conventional techniquessuch as filtering, decanting, centrifuging and the like. Drying may becarried out at 50EC in a vacuum oven.

Fluvastatin Sodium Crystal Form IV

Fluvastatin sodium Form IV produces a PXRD diffractogram withcharacteristic peaks at 3.6, 4.0, 9.8, 10.8 and 22.0±0.2 degreestwo-theta and additional peaks at 6.5, 12.8, 16.3, 16.9, 17.2, 18.3,19.5, 20.6 and 22.9±0.2 degrees two-theta (FIG. 4). Fluvastatin sodiumForm IV produced the DSC thermogram shown in FIG. 5, in which a mainendothermic peak can be seen below 70° C. and at about 120° C. The watercontent of the sample, measured by Karl Fisher, is about 4 wt. %. Theweight loss by TGA is 8.3%. The IR spectrum of fluvastatin sodium FormIV is shown in FIGS. 6, 6 a and 6 b.

Fluvastatin sodium Form IV can be prepared by dissolving fluvastatinsodium in refluxing tetrahydrofuran (“THF”) and adding dropwise organicanti-solvents like chloroform, dichloromethane, 1,2-dichloroethane,diethyl ether and n-pentane to the refluxing solution. Form IV shouldprecipitate from the refluxing mixture. The mixture may be maintained atreflux temperature for any amount of time necessary to achieve thedesired yield of Form IV. Afterwards the mixture is allowed to cool toroom temperature and Form IV can be isolated by a known method ofisolation such as filtering, decanting, centrifuging and the like,preferably filtering under nitrogen stream. Fluvastatin sodium Form IValso can be prepared by the same procedure, but substituting butan-1-ol,1,4-dioxane or propan-2-ol for the THF and using cyclohexane or methylt-butyl ether (“MTBE”) as the anti-solvent.

Fluvastatin Sodium Crystal Form IV-1

Fluvastatin sodium Form IV-1 produces a PXRD diffractogram withcharacteristic peaks at 3.6, 4.0, 9.6, 18.5 and 22.2±0.2 degreestwo-theta and other peaks at 6.6, 10.4, 11.0, 17.3, 19.5, 20.1, 20.7 and21.3≦0.2 degrees two-theta (FIG. 7). Fluvastatin sodium Form IV-1produced the DSC thermogram shown in FIG. 8, in which the mainendothermic peaks can be seen below 70° C. and at about 120° C. Thewater content measured by Karl Fisher, is about 2.1-2.6 wt. %. Theweight loss by TGA is about 10.5 wt. %. The IR spectrum of fluvastatinsodium Form IV-1 is shown in FIGS. 9, 9 a and 9 b.

Fluvastatin sodium Form IV-1 can be prepared by dissolving fluvastatinsodium in THF or 1,4-dioxane at reflux, and adding dropwise n-heptane orMTBE. Fluvastatin sodium Form IV-1 can also be prepared by dissolvingfluvastatin sodium in butan-2-ol and recrystallizing it during reflux.

Fluvastatin Sodium Crystal Form V

Fluvastatin sodium Form V produces a PXRD diffractogram (FIG. 10) withcharacteristic peaks at 3.8, 6.3, 9.5 and 21.2±0.2 degrees two-theta.

Two process for making Form V have been discovered to date, both ofwhich employ fluvastatin Form B as the starting material. According toone procedure, Form B is dissolved in refluxing butan-1-ol. After aclear solution is obtained, either by complete dissolution or filteringthe solution, heptane is slowly added to the refluxing solution.Thereafter, the solution is cooled and the precipitate is recovered.According to another procedure, Form B is dissolved in a solvent systemthat is a 5:2:1 ternary mixture of ethanol:ethyl acetate:propan-1-ol atreflux temperature. After a clear solution is obtained, either bycomplete dissolution or filtering the solution, n-hexane is slowly addedto the refluxing solution. The solution is then cooled to ambienttemperature and maintained until a precipitate is formed. In eitherprocedure, the product may be separated from the diluent by conventionaltechniques such as filtering, decanting, centrifuging and the like.Drying may be carried out at 50EC in a vacuum oven.

Fluvastatin Sodium Crystal Form VI

Fluvastatin sodium Form VI produces a PXRD diffractogram withcharacteristic peaks at 3.7, 4.7, 5.7, 10.9, 12.2 and 19.9±0.2 degreestwo-theta and other peaks at 9.1, 9.6, 14.3 16.3, 16.9, 20.4 and21.3±0.2 degrees two-theta (FIG. 11). Fluvastatin sodium Form VIproduced the DSC thermogram shown in FIG. 12, in which the mainendothermic peaks can be seen below 90° C. and at about 130° C. Thewater content measured by Karl Fisher is 5.0-5.6 wt. %. The weight lossby TGA is about 12%. Fluvastatin sodium Form VI was stable afterexposure to relative humidities between 0-40% RH for 12 days andequilibrated at water contents between 3-5%. At higher relativehumidities, it transformed to fluvastatin sodium form VII and Form D.The IR spectrum of fluvastatin sodium Form VI is shown in FIGS. 13, 13 aand 13 b.

Fluvastatin sodium Form VI can be prepared by dissolving fluvastatinsodium in DMF at room temperature and adding dropwise organicanti-solvents like diethyl ether or hexanes to precipitate the material.The mixture may be cooled using an ice-bath. Form VI can be separatedfrom the DMF and anti-solvent by methods known in the art such asfiltering, decanting centrifuging and the like, preferably filteringunder nitrogen stream.

Fluvastatin sodium Form VI also can be prepared directly from a loweralkyl ester of fluvastatin. The starting material is dissolved in asolution of about one molar equivalent of sodium hydroxide in a solventsystem selected from the group consisting of methanol, ethanol, mixturesof methanol and water and mixtures of butan-1-ol and water. Thepreferred methanol:water mixture is 91% methanol, 9% water and thepreferred butan-1-ol:water mixture is 94% butan-1-ol, 6% water. Thesolvent system is preferably heated, e.g. to reflux temperature, toaccelerate conversion of any lactone that may be present to the sodiumsalt, which process can be monitored by HPLC. Once the starting materialhas completely dissolved. an anti-solvent selected from the groupconsisting of acetonitrile and acetone is added dropwise to the solutionat elevated temperature to induce precipitation. After cooling themixture to ambient temperature, Form VI can be isolated by conventionaltechniques such as filtering, decanting, centrifuging and the like.Drying may be carried out at 50EC in a vacuum oven.

Fluvastatin Sodium Crystal Form VII

Fluvastatin sodium Form VII produces a PXRD diffractogram withcharacteristic peaks at 3.7, 4.3, 5.8, 8.6 and 20.7±0.2 degreestwo-theta and other peaks at 10.8, 12.3, 13.7, 15.8, 17.3, 19.4, 22.0,23.9, 25.2, 26.2 and 27.6 degrees two-theta (FIG. 14). Fluvastatinsodium Form VII produced the DSC thermogram shown in FIG. 15, in whichthe main endothermic peaks can be seen below 90° C. and at about 130° C.The water content, measured by Karl Fisher is about 4.1-4.5 wt. %. Theweight loss by TGA 13-14 wt. %. The IR spectrum of fluvastatin sodiumForm VII is shown in FIGS. 16, 16 a and 16 b.

Fluvastatin sodium Form VII was stable after exposure to relativehumidities between 20-60% RH for 11 days and equilibrated at watercontents between 1.4-8.6%. After exposure to 80% RH for 11 days, FormVII transformed to novel Form XX (water content: about 19%), and afterexposure to 100% RH for 11 days Form VII transformed to novel Form XIV(water content: about 17%). The results are summarized in the nexttable.

Water uptake (%) and crystal form of Fluvastatin sodium Form VIIequilibrated at different relative humidities for 11 days Water ContentWeight Loss Crystal RH (%) by KF (%) by TGA (%) Form 20 1.4-4.8 8.4 VII40 3.5-4.8 10.1 VII 60 6.6-8.6 9.6 VII 80 18.7-19.5 19.0 XX 100 16.617.6 XIV

Fluvastatin sodium Form VII can be prepared by dissolving fluvastatinsodium in N,N-dimethylformamide (“DMF”) at room temperature, and addingdropwise an organic anti-solvent like chloroform, MTBE, dichloromethane,cyclohexane or 1,2-dichloroethane to induce precipitation. The mixturemay be cooled using an ice-bath to enhance recovery of Form VII. FormVII can be isolated by methods known in the art such as filtering,decanting, centrifuging and the like, preferably by filtering under anitrogen stream.

Fluvastatin sodium Form VII also can be prepared by suspendingfluvastatin sodium, preferably Form B, in DMF at room temperature andisolating it by methods known in the art such as filtering, decanting,centrifuging and the like, preferably by filtering under a nitrogenstream.

Another way of making fluvastatin sodium Form VII starts from a loweralkyl ester of fluvastatin. The starting material is dissolved in asolution containing about one molar equivalent of sodium hydroxide in asolvent selected from the group consisting of butan-1-ol and mixtures ofwater and propan-2-ol. The preferred mixture of water and propan-2-olcontains about 8% water and 92% propan-2-ol. The starting material ispreferably dissolved at elevated temperature, e.g. the refluxtemperature of the solvent. Once a solution has been obtained, ananti-solvent, either acetone, acetonitrile or MTBE, is added to themixture at elevated temperature to induce precipitation.

Alternatively, the lower alkyl ester of fluvastatin can be taken up inmethanol at ambient or elevated temperature, preferably ambienttemperature, to form a saturated solution. A saturated solution can beprepared by forming an unsaturated solution and then evaporating solventuntil solids or turbidity appears. Then, the solution can be heated,preferably to reflux temperature, until all of the solids areredissolved. Next in this process, acetonitrile is added dropwise to thesolution to induce precipitation of fluvastatin sodium Form VII.

In yet another alternative process starting from the lower alkyl esterof fluvastatin, the starting material is dissolved in acetonitrile. Toeffect dissolution, the acetonitrile can be heated to 40EC. Then, asolution of sodium hydroxide in ethanol is added to the solution. Theresulting mixture becomes turbid and over time an oily phase mayseparate. If this occurs, the mixture should be heated until the oilgoes into solution. Then, Form VII can be precipitated by cooling orallowing the solution to cool.

After allowing the mixture to cool to ambient temperature Form VII canbe isolated by conventional techniques such as filtering, decanting,centrifuging and the like. Preferably, the liquids are separated byvacuum filtration under an inert gas like nitrogen. A suitable conditionfor drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form IX

Fluvastatin sodium Form IX produces a PXRD diffractograrn (FIG. 17) withcharacteristic peaks at 3.4, 10.0 and 19.7±0.2 degrees two-theta.

Form IX can be prepared by crystallization from a variety of solventsystems following procedures described in greater detail in theExamples. Briefly, Form IX can be precipitated from a solution in1,4-dioxane by addition of dichloromethane; from a solution in ethanolby addition of ethyl acetate, diethyl ether or n-pentane; or from amixture of ethanol and methanol by addition of hexanes. In addition,Form IX can be prepared by refluxing a suspension of Form B in ethylacetate.

Alternatively, Form IX can be prepared directly from a lower alkyl esterof fluvastatin such as fluvastatin methyl ester. The ester is dissolvedin a solution of about one molar equivalent of sodium in ethanol. Thesodium can be conveniently provided by dissolving the appropriatequantity of sodium hydroxide pellets in water, while exercising cautionsince the dissolution in water is highly exothermic. The solution isheated for a sufficient period of time to hydrolyze the ester, typicallyseveral hours. Then, a large excess (e.g. 7× v/v) of propan-2-ol isadded to the solution. The mixture is then cooled to ambient temperatureand maintained until a precipitate forms in the flask.

Form IX can be conventionally separated from the solvent or diluent by aknown method of isolation such as filtering, decanting, centrifuging andthe like, preferably filtering under a nitrogen stream.

Fluvastatin Sodium Crystal Form IX-1

Fluvastatin sodium Form IX-1 produces a PXRD diffractogram (FIG. 18)with characteristic peaks at 3.4, 6.6, 10.0, 13.2, 19.8±0.2 degreestwo-theta.

We have discovered a multitude of ways to make Form IX-1, which areexemplified by starting from fluvastatin Form B. For the sake ofbrevity, please refer to the Examples for the particulars of how it canbe made.

Fluvastatin Sodium Crystal Form XI

Fluvastatin sodium Form XI produces a PXRD diffractogram withcharacteristic peaks at 3.3, 3.8, 4.6, 8.3, 10.2 and 25.1±0.2 degreestwo-theta and other peaks at 7.2, 11.4, 12.4, 13.6, 16.0, 16.9, 17.4,20.4, 21.3, 21.9 and 23.1±0.2 degrees two-theta (FIG. 19). Fluvastatinsodium Form XI produced the DSC thermogram shown in FIG. 20 in which onemain endothermic peak can be seen at about 150° C. The water content ofthe sample is about 4-6 wt. %. The weight loss by TGA is 6-8%. The IRspectrum of fluvastatin sodium Form XI is shown in FIGS. 21, 21 a and 21b.

Fluvastatin sodium Form XI was stable after exposure to relativehumidities between 20-60% RH for 11 days and equilibrated at watercontents between 1.1-5.6%. After exposure to 80% and 100% RH for 11days, Form XI transformed to novel Form XIX (water content: about19-28%). The results are summarized in the next table.

Water uptake (%) and Crystal Form of Fluvastatin Sodium Crystal Form XIEquilibrated at Different Relative Humidities for 11 Days Water ContentWeight Loss Crystal RH (%) by KF (%) by TGA (%) Form 0 2.0-2.4 6.5 XI 201.1-5.6 5.0 XI 40 3.0-3.6 4.5 XI 60 3.5-3.6 4.7 XI 80 19.5-22.6 22.0 XIX100 28.0-28.4 26.2 XIX

Fluvastatin sodium Form XI can be prepared by dissolving fluvastatinsodium, preferably Form B, in refluxing butan-2-ol. During reflux, thefluvastatin sodium recrystallizes in Form XI. Addition of organicanti-solvents like hexanes, n-pentane, MTBE, diethyl ether, n-heptaneand chloroform at reflux tends to increase the yield of precipitate. Themixture may be maintained at reflux temperature for any amount of timenecessary to achieve the desired yield of Form XI. Afterwards, themixture is allowed to cool to room temperature and Form XI can beisolated by a known method of isolation such as filtering, decanting,centrifuging and the like, preferably filtering under a nitrogen stream.

Fluvastatin Sodium Crystal Form XI-2

Fluvastatin sodium Form XI-2 produces a PXRD diffractogram withcharacteristic peaks at 3.5, 3.8, 4.6, 10.4 and 18.5±0.2 degreestwo-theta and other peaks at 8.5, 11.2, 12.1, 16.4, 17.0, 17.7, 20.9,21.2, 21.7, 22.2 and 23.6±0.2 degrees two-theta (FIG. 22). Fluvastatinsodium Form XI-2 produced the DSC thermogram shown in FIG. 23, in whichtwo main endothermic peaks can be seen below 80° C. and at about 145 °C. The water content of the sample is about 1.9-3.2 wt. %. The weightloss by TGA is 7.7%. Fluvastatin sodium form XI-2 was stable afterexposure to relative humidities between 0-60% RH for 11 days andequilibrated at water contents between 5-7%. At higher relativehumidities it transformed into Form D. The IR spectrum of fluvastatinsodium Form XI-2 is shown in FIGS. 24, 24 a and 24 b.

Fluvastatin sodium Form XI-2 can be prepared by dissolving fluvastatinsodium in refluxing propan-1-ol and adding dropwise organicanti-solvents like hexanes, MTBE and dichloromethane. The mixture may bemaintained at reflux temperature for any amount of time necessary toachieve the desired yield of Form XI-2. Afterwards, the mixture isallowed to cool to room temperature and Form XI-2 can be isolated by aknown method of isolation like filtering, decanting, centrifuging andthe like, preferably filtering under nitrogen stream.

Fluvastatin Sodium Crystal Form XII

Fluvastatin sodium Form XII produces a PXRD diffractogram (FIG. 25) withcharacteristic peaks at 3.1, 6.5, 9.8, 17.6, 25.9 and 30.9±0.2 degreestwo-theta.

Form XII is prepared by crystallization from a mixture of butan-1-ol and1,4-dioxane. According to a preferred process, Form B is dissolved inrefluxing butan-1-ol. 1,4-Dioxane is then added to the refluxingsolution until it becomes turbid. Thereafter, the mixture is cooled toambient temperature at which point additional 1,4-dioxane may be addedto enhance recovery of Form XII. Form XII can be separated from thesolvent system by conventional techniques such as filtering, decanting,centrifuging and the like, preferably filtering under an inertatmosphere like nitrogen. The separated Form XII may be dried. Asuitable drying condition is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XIII

Fluvastatin sodium Form XIII produces a PXRD diffractogram (FIG. 26)with characteristic peaks at 3.8, 5.6, 12.3 and 20.6±0.2 degreestwo-theta.

Form XIII can be prepared by suspending fluvastatin sodium Form B inacetonitrile, which is preferably done at elevated temperature and thencooling the suspension to reduced temperature such as 10EC. Form XIIIcan be separated from the acetonitrile by conventional techniques suchas filtering, decanting, centrifuging and the like, preferably filteringunder an inert atmosphere like nitrogen. The separated Form XIII may bedried. A suitable drying condition is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XV

The material that was received in Israel in response to a commercialorder placed to the Zhejiang Hisun Pharmaceutical Co., Ltd. 46 WaishaRd., Jiaojiang District, Taizhou City, Zhejiange Province, China, wassubjected to PXRD analysis at our facility in Israel and produced thePXRD diffractogram depicted in FIG. 30, which is distinct from thediffractograms produced by each of the other solid state forms offluvastatin sodium disclosed herein. We have designated this solid stateform of fluvastatin sodium Form XV. Form XV has been found useful forproducing certain novel solid state forms of fluvastatin sodium, asdescribed below.

Fluvastatin Sodium Crystal Form XVI

Fluvastatin sodium Form XVI produces a PXRD diffractogram withcharacteristic peaks at 3.8 and 7.0+0.2 degrees two-theta and otherpeaks at 4.3, 10.2, 10.7, 11.2, 15.6, 17.8, 18.4 and 19.5±0.2 degreestwo-theta. (FIG. 31). Fluvastatin sodium Form XVI produced the DSCthermogram shown in FIG. 32, in which broad endothermic peaks can beseen below 80° C. and between 100-150° C. The water content of thesample is about 3-4 wt. %. The weight loss by TGA is 8.7 wt. %. The IRspectrum of fluvastatin sodium Form XVI is shown in FIGS. 33, 33 a and33 b.

Fluvastatin sodium Form XVI can be prepared by dissolving fluvastatinsodium in refluxing propan-2-ol and adding dropwise an organicanti-solvent like dichloromethane. The mixture may be maintained atreflux temperature for any amount of time necessary to achieve thedesired yield of Form XVI. Afterwards, the mixture is allowed to cool toroom temperature and Form XVI can be isolated by a known method ofisolation like filtering, decanting, centrifuging and the like.

Fluvastatin Sodium Crystal Form XVII

Fluvastatin sodium Form XVII produces a PXRD diffractogram withcharacteristic peaks at 3.5 (broad), 5.4, 5.8 and 13.8±0.2 degreestwo-theta and other peaks at 10.8, 14.8, 16.4, 19.4, 21.5 and 22.7±0.2degrees two-theta. (FIG. 34). Fluvastatin sodium Form XVII produced theDSC thermogram shown in FIG. 35, in which two broad endothermic peakscan be seen at 80 and at about 113° C. respectively. The weight loss byTGA is 8.4 wt. %.

Fluvastatin sodium Form XVII can be prepared by dissolving fluvastatinsodium in propan-1-ol and recrystallizing it from the stirred solution.In a preferred embodiment, the recrystallization is carried out atelevated temperature.

Fluvastatin Sodium Crystal Form XVIII

Fluvastatin sodium Form XVIII produces a PXRD diffractogram withcharacteristic peaks at 3.4, 8.4, 10.0 and 10.9±0.2 degrees two-thetaand other peaks at 11.7, 12.6, 15.8, 17.4, 18.0, 18.8, 20.0, 20.7 and21.3±0.2 degrees two-theta. (FIG. 36). Fluvastatin sodium Form XVIIIproduced the DSC thermogram shown in FIG. 37, in which two endothermicpeaks can be seen below 70° C. and at about 180° C. The water content ofthe sample is about 4 wt. %. The loss on drying shown by TGA is about 4wt. %. Fluvastatin sodium form XVIII is a monohydrate. The IR spectrumof fluvastatin sodium Form XVIII is shown in FIGS. 38, 38 a and 38 b.

Fluvastatin sodium Form XVIII can be prepared by suspending fluvastatinsodium in refluxing methylethyl ketone (MEK). The mixture may bemaintained at reflux temperature for any amount of time necessary toachieve the desired yield of Form XVIII. Afterwards, the mixture isallowed to cool to room temperature and Form XVIII can be isolated by aknown method of isolation such as filtering, decanting, centrifuging,distilling and the like, preferably filtering under a nitrogen stream ordistillation.

Fluvastatin Sodium Crystal Form XIX

Fluvastatin sodium Form XIX produces a PXRD diffractogram withcharacteristic peaks at 3.4, 10.1, 13.5 and 18.0±0.2 degrees two-thetaand other peaks at 6.8, 20.1, 21.8 and 25.6±0.2 degrees two-theta. (FIG.39). Fluvastatin sodium Form XIX produced the DSC thermogram shown inFIG. 40, in which one main endothermic peak can be seen at about 80° C.The water content of the sample is 19-28 wt. %. The weight loss by TGAis 22-26 wt. %. Fluvastatin sodium Form XIX is in hexahydrate,8-hydrate, and 9-hydrate forms. The IR spectrum of fluvastatin sodiumForm XIX is shown in FIGS. 41, 41 a and 41 b.

Fluvastatin sodium Form XIX can be prepared by exposing Form XI, IV-1 orXVI to an atmosphere of elevated humidity ranging of about 60% to about100% RH.

Fluvastatin Sodium Crvstal Form XIX-1

Fluvastatin sodium Form XIX-1 produces a PXRD diffractogram (FIG. 42)with characteristic peaks at 3.5, 10.4, 11.9, 14.0, 22.5±0.2 degreestwo-theta and other peaks at 17.5, 17.8, 18.0, 18.3, 25.4±0.2 degreestwo-theta. The water content of fluvastatin Form XIX-1 measured by KarlFisher analysis is about 8% by weight. The weight loss by TGA is about7% by weight. Fluvastatin sodium Form XIV is a dihydrate.

Fluvastatin sodium Form XIX-1 can be prepared by forming a heterogeneousmixture of fluvastatin sodium Form XI and water and maintaining themixture for a period of time sufficient to achieve the desired yield ofForm XIX-1. The mixture may be stirred and preferably is stirred forabout 2 hours to about 15 hours, with about 5 hours being especiallypreferred. The product may then be recovered from the mixture byconventional techniques such as filtration.

The recovered wet product may then be optionally dried. Drying may becarried out at a preferred temperature range of from about 40EC to about60EC, for about 12 to about 48 hours.

Fluvastatin Sodium Crystal Form XX

Fluvastatin sodium Form XX produces a PXRD diffractogram withcharacteristic peaks at 3.5, 10.1, 13.5, 18.0 and 20.8±0.2 degreestwo-theta and other peaks at 5.9 and 12.4 degrees two-theta. (FIG. 43).Fluvastatin sodium Form XX produced the DSC thermogram shown in FIG. 44,in which one main endothermic peak is seen below about 130° C. The watercontent of the sample is about 19 wt. %. The loss on drying by TGA isabout 19 wt. %. Fluvastatin sodium Form XX is a hexahydrate. The IRspectrum of fluvastatin sodium Form XX is shown in FIGS. 45, 45 a and 45b.

Fluvastatin Form XX can be prepared by exposing fluvastatin sodium FormVII to an atmosphere of relative humidity of 80% or higher for a periodof time sufficient to effect the conversion of Form XX.

In the case of fluvastatin sodium Forms XI, XIV, XVIII, XIX and XX, theTGA and Karl Fisher analyses were in close agreement, which is taken asan indication that those samples are mainly hydrated forms.

In fluvastatin sodium Forms IV, IV-1, VI, VII and XI-2, the TGA analysisexceeded that of Karl Fisher, which is taken as an indication that aconsiderable quantity of organic solvent was present. After exposure at60% relative humidity for 11 days , the gap between TGA and KF resultsdecreased (see below Forms VII and XI stored at different relativehumidities), indicating that the level of organic solvent decreased. Asa consequence, exposure to humidity is a useful method minimize theorganic solvent present in fluvastatin sodium.

Fluvastatin Sodium Crystal Form XXII

Fluvastatin sodium Form XXII produces a PXRD diffractogram (FIG. 46)with characteristic peaks at 3.2, 12.4, and 18.3±0.2 degrees two-thetaand other peaks at 6.4, 9.5, 15.6 and 21.4 degrees two-theta.

Form XXII can be prepared by exposing fluvastatin sodium Form XV towater vapor. Preferably, Form XV is maintained under an atmosphere of100% relative humidity at ambient temperature. Substantially completeconversion is achieved over a period of weeks, typically about twoweeks.

Fluvastatin Sodium Crystal Form XXIII

Fluvastatin sodium Form XXIII produces a PXRD diffractogram (FIG. 47)with characteristic peaks at 3.6, 4.0, 4.4, 17.1 and 19.3±0.2 degreestwo-theta and other peaks at 6.2, 7.2, 9.3, 10.2 and 18.6 degreestwo-theta.

Form XXIII can be prepared by dissolving about 1:20 (w/v) of fluvastatinsodium Form B in refluxing propan-1-ol. In a matter of hours aftercomplete dissolution, fluvastatin sodium should begin to precipitate inForm XXIII. After the initial crystals form, the mixture can be cooledor allowed to cool to ambient temperature to complete thecrystallization yielding Form XXIII. Form XXIII can be separated fromthe propan-1-ol by conventional techniques such as filtering, decanting,centrifuging and the like, preferably filtering under an inertatmosphere like nitrogen. The separated Form XXIII may be dried. Asuitable drying condition is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XXIV

Fluvastatin sodium Form XXIV produces a PXRD diffractogram (FIG. 48)with characteristic peaks at 3.4, 10.2, 13.6, 17.9 and 18.7±0.2 degreestwo-theta and other peaks at 6.9, 10.7, 12.0, 22.5 and 25.4 degreestwo-theta.

Form XXIV can be prepared from fluvastatin sodium Form B and fluvastatinForm XV. Form XXIV can be obtained from these forms by crystallizationfrom water. When starting from Form XV, the starting material isdissolved in refluxing water. After a period of hours to a few daysfollowing cooling of the solution to ambient temperature, Form XXIVcrystallizes out of solution. Form XXIV can be separated from the waterby conventional techniques such as filtering, decanting, centrifugingand the like, preferably filtering under an inert atmosphere likenitrogen. The separated Form XXIV may be dried. A suitable dryingcondition is 50EC under vacuum. When starting from Form B, the startingmaterial can be dissolved in the water at ambient temperature. If FormXXIV does not crystallize, the procedure can be modified as follows.Diethyl ether is added to the vessel containing the solution andcontacted with the solution for several minutes. Then, the phases areseparated and the aqueous phase is lyophilized to obtain a residue thatis fluvastatin sodium Form XXIV.

Fluvastatin Sodium Crystal Form XXVI

Fluvastatin sodium Form XXVI produces a PXRD diffractogram (FIG. 49)with characteristic peaks at 3.8, 15.0, 18.5, 21.6 and 25.8±0.2 degreestwo-theta and other peaks at 11.7, 15.9, 16.2, 24.3 and 35.2 degreestwo-theta.

Form XXVI can be prepared by dissolving about 1:7 (w/v) of fluvastatinsodium Form B in a 20:1 mixture of 1,4-dioxane:water. The mixture isrefluxed until a clear solution is obtained. Then the mixture is cooledor allowed to cool to induce precipitation of fluvastatin sodium in FormXXVI. Form XXVI can be separated from the water and 1,4-dioxane byconventional techniques such as filtering, decanting, centrifuging andthe like, preferably filtering under an inert atmosphere like nitrogen.The separated Form XXVI may be dried. A suitable drying condition is50EC under vacuum.

Fluvastatin Sodium Crystal Form XXVII

Fluvastatin sodium Form XXVII produces a PXRD diffractogram (FIG. 50)with characteristic peaks at 3.3, 3.9, 15.9, 18.4 and 21.6±0.2 degreestwo-theta and other peaks at 8.4, 15.0, 17.9, 24.3 and 25.7±0.2 degreestwo-theta.

The initial steps for preparing Form XXVII are the same as for preparingForm XXVI. Form B is dissolved in a refluxing 20:1 mixture of1,4-dioxane:water. However, at reflux temperature 1.5 volumes of hexanesis slowly added to the solution. Thereafter, the mixture is cooled toambient temperature after which fluvastatin sodium crystalizes in FormXXVII from the mixture. Form XXVII can be separated from the solution byconventional techniques such as filtering, decanting, centrifuging andthe like, preferably filtering under an inert atmosphere like nitrogen.The separated Form XXVII may be dried. A suitable drying condition is50EC under vacuum.

Fluvastatin Sodium Crystal Form XXIX

Fluvastatin sodium Form XXIX produces a PXRD diffractogram withcharacteristic peaks at 4.4, 5.9, 6.8, 7.9, 10.8±0.2 degrees two-thetaand other peaks at 14.3, 15.6, 17.5, 19.7, 21.3, 22.7±0.2 degreestwo-theta (FIG. 51).

Fluvastatin sodium Form XXIX can be prepared by forming a heterogeneousmixture of fluvastatin sodium Form XV and 1,4-dioxane and maintainingthe heterogeneous mixture until substantially all of the Form XV isconverted into Form XXIX. Preferably, the conversion is accelerated byheating the heterogeneous mixture.

Under an especially preferred set of conditions, the heterogeneousmixture is heated to the reflux temperature of 1,4-dioxane andmaintained at reflux for about 16 hours. Then, Form XXIX is separatedfrom the 1,4 dioxane by cooling the mixture and filtering the mixtureunder a nitrogen flow. Thereafter, Form XXIX may be conventionallydried.

Fluvastatin Sodium Crystal Form XXX

Fluvastatin sodium Form XXX produces a PXRD diffractogram withcharacteristic peaks at 5.4, 5.8, 10.8, 13.8, 14.8±0.2 degrees two-thetaand other peaks at 16.4, 19.0, 19.5, 20.2, 20.8, 21.5, 22.7±0.2 degreestwo-theta (FIG. 52). The water content of the sample, measured by KarlFisher, is about 4% by weight. The weight loss by TGA is about 10%.

Fluvastatin sodium Form XXX can be prepared by forming a heterogeneousmixture of fluvastatin sodium Form XV and one or a mixture of certainselected organic liquids. Liquids that have been found suitable includemethylethylketone (“MEK”), tetrahydrofuran (“THF”), acetone, butan-2-oland butan-1-ol. The heterogeneous mixture is maintained untilsubstantially all of the Form XV is converted into Form XXX. Preferably,the conversion is accelerated by heating the heterogeneous mixture.

Under an especially preferred set of conditions, the heterogeneousmixture is heated to the reflux temperature of organic liquid used andmaintained at reflux for about 16 hours. Then, Form XXX is separatedfrom the organic liquid by cooling the mixture and filtering the mixtureunder a nitrogen flow. Thereafter, Form XXX may be conventionally dried.

Fluvastatin sodium Form XXX also can be prepared directly from a loweralkyl ester of fluvastatin by precipitation from a solution containingan excess of sodium. The preferred excess of sodium is about 1.5 molarequivalents. According to a preferred procedure, the starting materialis added to a solution of sodium hydroxide in mixture containing wateras a minor component and methanol as a major component and the resultingmixture is heated, e.g. to the reflux temperature of the solvent, untila clear solution is obtained. Acetone is then added to the solution atelevated temperature to induce precipitation of Form XXX. After coolingto ambient temperature. Form XXX can be separated from the methanol andwater by conventional techniques such as filtering, decanting,centrifuging and the like. Preferably, the water is separated by vacuumfiltration under an inert gas like nitrogen. A suitable condition fordrying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XXXI

Fluvastatin sodium Form XXXI produces a PXRD diffractogram withcharacteristic peaks at 5.3, 6.1, 6.5, 11.9, 13.2±0.2 degrees two-theta,and other peaks at 8.0, 8.5, 9.3, 16.3, 18.3, 20.2, 20.6, 21.1±0.2degrees two-theta (FIG. 53). The water content of fluvastatin sodiumForm XXXI measured by Karl Fisher analysis is about 16% by weight. Theweight loss by TGA is about 10% by weight. Fluvastatin sodium Form XXXIis a tetrahydrate.

Fluvastatin sodium Form XXXI can be prepared by forming a heterogeneousmixture of fluvastatin sodium Form XV and ethanol and maintaining theheterogeneous mixture until substantially all of the Form XV isconverted into Form XXXI. Preferably, the conversion is accelerated byheating the heterogeneous mixture.

Under an especially preferred set of conditions, the heterogeneousmixture is heated to the reflux temperature of ethanol and maintained atreflux for about 23 hours. Then, Form XXXI is separated from the ethanolby cooling the mixture and filtering the mixture under a nitrogen flow.Thereafter, Form XXXI may be conventionally dried.

Fluvastatin Sodium Crystal Form XXXIII

Fluvastatin sodium Form XXXIII produces a PXRD diffractogram (FIG. 54)with characteristic peaks at 4.0, 5.5, 8.0, 9.1, 13.4, 16.6, 21.2±0.2degrees two-theta and other peaks at 6.6, 8.8, 10.4, 11.6, 12.0, 14.1,14.8, 16.1, 17.9, 18.5, 19.7, 20.3, 24.3, 24.9, 26.7±0.2 degreestwo-theta. The water content of the sample measured by Karl Fisher isabout 7% by weight. The weight loss by TGA is about 7%. The watercontent measured may reach about 10% by weight. Fluvastatin sodium FormXXXIII is in dihydrate and hemipentahydrate form.

Fluvastatin sodium Form XXXIII can be prepared by forming aheterogeneous mixture of fluvastatin sodium Form XV or Form B andethanol, preferably absolute ethanol and maintaining the mixture for aperiod of time sufficient to achieve the desired yield of Form XXXIII.The mixture preferably is stirred for about 5 hours to about 48 hoursand heated to reflux temperature while stirring. The product may then berecovered from the mixture by conventional techniques such as filtering,decanting, centrifuging and the like. The recovered wet product may thenbe optionally dried. Drying may be carried out at a preferredtemperature range of from about 40EC to about 60EC, for about 12 toabout 48 hours.

Fluvastatin sodium Form XXXIV

Fluvastatin sodium Form XXXIV produces a PXRD diffractogram (FIG. 55)with characteristic peaks at 5.4, 6.1, 7.6, 18.5, 21.1±0.2 degreestwo-theta and other peaks at 8.8, 9.3, 12.4, 13.1, 14.3, 15.2, 15.9,17.2, 17.6, 20.5, 22.2, 24.1, 25.4, 26.2±0.2 degrees two-theta. Thewater content of Form XXXIV as measured by Karl Fisher analysis is about10% by weight. The weight loss by TGA is about 20%.

Fluvastatin sodium Form XXXIV can be prepared by forming a heterogeneousmixture of fluvastatin Form XV and dimethyl sulfoxide (“DMSO”) andmaintaining the mixture for a period of time sufficient to achieve thedesired yield of Form XXXIV. The mixture preferably is stirred about 5hours to about 48 hours and heated while stirring, yet more preferablyheated to about 80EC or higher temperature. The product may then berecovered from the slurry by conventional techniques such as filtering,decanting, centrifuging and the like. The recovered wet product may thenbe optionally dried. Drying may be carried out at a preferredtemperature range of from about 40EC to about 60EC, for about 12 toabout 48 hours.

Fluvastatin sodium Form XXXV

Fluvastatin sodium Form XXXV produces a PXRD diffractogram (FIG. 56)with characteristic peaks at 5.4, 6.0, 9.9, 14.8, 21.0±0.2 degrees 2theta and other peaks at 16.7, 18.6, 19.8, 22.6±0.2 degrees two-theta.The water content of this sample measured by Karl Fisher is about 15% byweight. The weight loss by TGA is about 31% by weight. Fluvastatinsodium Form XXXVII is a hemipentahydrate.

Fluvastatin sodium Form XXXV may be prepared by forming a heterogeneousmixture of fluvastatin sodium Form XV in N,N dimethyl formamide (“DMF”)and maintaining the mixture for a period of time sufficient to achievethe desired yield of Form XXXV. The mixture preferably is stirred forabout 5 hours to about 48 hours. The mixture is preferably heated whilestirring. Yet more preferably, the stirred mixture is heated to atemperature of about 80EC or higher. The product may then be recoveredfrom the mixture by conventional techniques such as filtering,decanting, centrifuging and the like. The recovered wet product may thenbe optionally dried. Drying may be carried out at a preferredtemperature range of from about 40EC to about 60EC, for about 12 toabout 48 hours.

Fluvastatin Sodium Crystal Form XXXVI

Fluvastatin sodium Form XXXVI produces a PXRD diffractogram (FIG. 57)having characteristic peaks at 3.0, 9.2, 11.5, 14.4 and 20.2±0.2 degreestwo-theta, and other peaks at 9.6, 12.3 and 12.8±0.2 degrees two-theta.

Form XXXVI can be prepared by suspending fluvastatin sodium Form XI-wet(obtained after filtration, but before drying) in water for a sufficientperiod time to effect the conversion (typically about 6 h). The productmay then be recovered from the suspension by conventional techniquessuch as filtering, decanting, centrifuging and the like. The recoveredwet product may then be optionally dried. A suitable condition fordrying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XXXVII

Fluvastatin sodium Form XXXVII produces a PXRD diffractogram havingcharacteristic peaks at 3.63, 10.36, 13.74, 17.93, 18.34±0.2 degreestwo-theta, and other peaks at 11.26, 12.16, 12.91, 19.44, 20.57±0.2degrees two-theta (FIG. 58). The water content of this sample measuredby Karl Fisher is about 9% by weight. The weight loss by TGA is about31% by weight.

Fluvastatin sodium Form XXXVII can be prepared by forming aheterogeneous mixture of fluvastatin sodium Form XI and water. Theweight ratio of Form XI to water is preferably about 0.5:1. The mixtureshould be maintained at ambient temperature. The conversion takes about5 h, 45 min. at 22 EC. Form XXXVII can then be separated from the waterby conventional means such as filtering, decanting, centrifuging and thelike. Preferably, the water is separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XXXVIII

Fluvastatin sodium Form XXXVIII produces a PXRD diffractogram havingcharacteristic peaks at 3.64, 4.66, 7.30, 8.84, 11.61±0.2 degreestwo-theta, and other peaks at 19.08, 19.65, 21.15, 22.59, 24.20±0.2degrees two-theta (FIG. 59). The water content of this sample measuredby Karl Fisher is about 6-7% by weight. The weight loss by TGA is about10-11% by weight.

Fluvastatin sodium Form XXXVIII can be prepared by forming aheterogeneous mixture of fluvastatin sodium Form XI and ethanol. Toobtain a product of highest polymorphic purity it is preferable to useabsolute ethanol. The ratio of Form XI to ethanol is preferably about0.2 g ml⁻¹, more preferably about 0.19 g ml⁻¹.

Under a particular preferred set of conditions the heterogeneous mixtureis heated until the ethanol boils and is maintained at that temperaturefor several hours until the conversion of Form XI to Form XXXVIII iscomplete. The conversion can be monitored by powder X-raydiffractometry. If the conversion is still not complete after severalhours (it took 16 hours in one of our experiments) then the mixture canbe held at elevated or ambient temperature until the conversion isconsidered to be sufficiently complete.

Form XXXVIII can then be separated from the ethanol by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the ethanol is separated by vacuum filtration under an inertgas like nitrogen. A suitable condition for drying the separated productis 50EC under vacuum.

Fluvastatin sodium Form XXXVIII also can be prepared from a lower alkylester of fluvastatin by taking it up in a solution of about one molarequivalent of sodium hydroxide in ethanol and then precipitating it byaddition of ethyl acetate to the mixture. Thereafter, Form XXXVIII canthen be separated from the ethanol and ethyl acetate by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the ethanol and ethyl acetate are separated by vacuumfiltration under an inert gas like nitrogen. A suitable condition fordrying the separated product is 50EC under vacuum.

Yet further, Form XXXVIII can be prepared by suspending fluvastatinsodium Form XI-wet in refluxing absolute ethanol, preferably for about16 h. Then the suspension is cooled to reduced temperature and theproduct is isolated by conventional means.

Fluvastatin Sodium Crystal Form XXXIX

Fluvastatin sodium Form XXXIX produces a PXRD diffractogram (FIG. 60)having characteristic peaks at 3.7, 4.5, 8.5, 17.8, 20.1±0.2 degreestwo-theta and other peaks at 6.9, 11.2, 16.8, 19.6 and 21.6±0.2 degreestwo-theta.

Form XXXIX can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The ester is dissolved ina solution of about one molar equivalent of sodium in ethanol. Thesodium can be conveniently provided by dissolving the appropriatequantity of sodium hydroxide pellets in water, while exercising cautionsince the dissolution in water is highly exothermic. The solution isheated for a sufficient period of time to hydrolyze the ester, typicallyseveral hours. Then, a large excess (e.g. 8× v/v) of propan-2-ol isadded to the solution. The mixture is then cooled to ambient temperatureand maintained until a precipitate forms in the flask.

Form XXXIX can then be separated from the solution by conventionalmeans. Form XXXIX unlike Form IX is obtained without use of water.

Fluvastatin Sodium Crystal Form XLI

Fluvastatin sodium Form XLI produces a PXRD diffractogram havingcharacteristic peaks at 3.75, 4.31, 9.10, 11.00±0.2 degrees two-thetaand other peaks at 5.60, 7.30, 7.55, 14.50, 18.04±0.2 degrees two-theta(FIG. 61). The water content of this sample measured by Karl Fisher isabout 9% by weight. The weight loss by TGA is about 9% by weight.Fluvastatin sodium Form XLI is a hemipentahydrate.

Fluvastatin sodium Form XLI can be prepared by precipitating fluvastatinsodium from a mixture of water and acetonitrile. Fluvastatin sodiumshould first be dissolved in water. The water may be heated in order toproduce a more concentrated solution and maximized recovery of Form XLI.Fluvastatin sodium can be dissolved to produce a solution of 0.375 gml⁻¹ or greater in water at 100EC. Of course, if all of the fluvastatinsodium does not go into solution or reprecipitates, additional watershould be added. Once a homogeneous solution has been formed,acetonitrile is added to the solution to induce precipitation of thefluvastatin sodium. The addition is done at whatever elevatedtemperature was used to dissolve the starting material or at highertemperature. The addition is dropwise and will generally require addinga excess of acetonitrile over the amount of water that was used. Forexample, we used a little less than four volumes of acetonitrile. Theresulting heterogeneous mixture is then allowed to cool. Beforeisolating the fluvastatin sodium Form XLI that precipitates. Therecovery can be improved by adding an addition portion of acetonitrileafter cooling.

Form XLI can then be separated from the water and acetonitrile byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the liquids are separated by vacuum filtration underan inert gas like nitrogen and washed with acetonitrile. A suitablecondition for drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XLII

Fluvastatin sodium Form XLII produces a PXRD diffractogram havingcharacteristic peaks at 3.4, 9.7, 11.0, 18.9±0.2 degrees two-theta andother peaks at 5.7, 14.8, 16.1, 17.0, 22.6±0.2 degrees two-theta (FIG.62). The water content of this sample measured by Karl Fisher is about4% by weight. The weight loss by TGA is about 5% by weight. Fluvastatinsodium Form XLII is a monohydrate.

Form XLII can be prepared from a fluvastatin-diol by dissolvingfluvastatin-diol in methyl ethyl ketone and then filtering the solution.Sodium hydroxide dissolved in methanol is then added to the solution andthe solution is stirred at room temperature to obtain a gelatinousprecipitate. The product is recovered by any conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the liquidsare separated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

According to another process for preparing fluvastatin sodium Form XLII,fluvastatin diol is dissolved in methanol at reflux temperature andsolid sodium hydroxide is added to the solution. The solution is stirredat room temperature to obtain a precipitate having a paste-likeconsistency. Ethyl acetate is added dropwise to the stirred solution.Then, the solution is cooled to form a slurry. The product is separatedfrom the solution by any conventional means such as filtering,decanting, centrifuging and the like. Preferably, the liquids areseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

According to yet another process for preparing fluvastatin sodium formXLII, fluvastatin-diol is completely dissolved in dichloromethane andthe solution is filtered. An ethanolic or methanolic solution of NaOH isadded to the solution. The solution is stirred at room temperature toobtain a precipitate and the product is separated by any conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the liquids are separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XLIII

Fluvastatin sodium Form XLIII produces a PXRD diffractogram havingcharacteristic peaks at 4.25, 5.29, 6.59, 8.60±0.2 degrees two-theta andother peaks at 12.75, 14.26±0.2 degrees two-theta (FIG. 63). The watercontent of this sample measured by Karl Fisher is about 9-11% by weight.The weight loss by TGA is about 12% by weight.

We have discovered two ways of making Form XLIII. It can be made byinducing precipitation from an aqueous solution by dropwise addition ofpropan-2-ol at elevated temperature. The preferred procedure is similarto that used to prepare Form XLI, except that propan-2-ol is usedinstead of acetonitrile. We prepared an aqueous solution with a threefold excess of water to fluvastatin sodium (ml g⁻¹). After obtaining ahomogenous solution, a three-fold excess of propan-2-ol to water (mlml⁻¹) was added to it at elevated temperature. The initial addition ofpropan-2-ol at elevated temperature causes crystals of Form XLIII toform. However, addition of another portion of propan-2-ol of about thesame amount after the mixture has cooled should be done to maximizerecovery of Form XLIII.

According to another process for preparing fluvastatin sodium FormXLIII, a lower alkyl ester of fluvastatin is dissolved in a solutioncontaining about one molar equivalent of sodium hydroxide in water. Oncea homogeneous solution of fluvastatin sodium is obtained, precipitationof the sodium salt is induced by addition of propan-2-ol. Formation ofthe salt and the initial addition of propan-2-ol are preferablyconducted at elevated temperature, e.g. 70EC. After cooling the solutionto ambient temperature, additional portions of propan-2-ol can be addedto increase recovery of Form XLIII. There is a tendency for the solutionto gel. As described in the examples, the gel can be broken by reheatingthe mixture and then cooling again.

Form XLIII can then be separated from the water and propan-2-ol ineither of the processes just described by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the liquidsare separated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form XLIV

Fluvastatin sodium Form XLIV produces a PXRD diffractogram havingcharacteristic peaks at 3.46, 4.05, 9.19, 10.14, 20.56±0.2 degreestwo-theta and other peaks at 6.26, 10.91, 11.12, 11.38, 15.98,20.02,22.21, 23.52, 25.45±0.2 degrees two-theta (FIG. 64). The watercontent of this sample measured by Karl Fisher is about 4-6% by weight.The weight loss by TGA is about 8-10% by weight.

Fluvastatin sodium Form XLIV can be prepared by forming a heterogeneousmixture of amorphous fluvastatin sodium in propan-2-ol. Preferably thetwo are used in a ratio of about 20 ml g⁻¹. The suspension should beheated to accelerate conversion. After cooling, Form XLIV can beseparated from the propan-2-ol by conventional means such as filtering,decanting, centrifuging and the like. Preferably, the propan-2-ol isseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Alternatively Form XLIV can be prepared directly from fluvastatin freeacid. According to a preferred embodiment of this method, the free acidis dissolved in acetone and a molar equivalent of ethanolic sodium(preferably prepared by dissolving an equivalent of sodium hydroxide inethanol) is added to the solution and the resulting mixture ismaintained until fluvastatin sodium Form XLIV precipitates. Form XLIVmay then be separated from the acetone and ethanol by conventional meansand dried. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Crystal Form XLV

Fluvastatin sodium Form XLV produces a PXRD pattern (FIG. 65) havingcharacteristic peaks at 3.7, 5.1, 10.7, 17.8 and 20.3±0.2 degreestwo-theta, and other peaks at 6.2, 14.5, 21.6, 22.6 and 25.2±0.2 degreestwo-theta.

Form XLV can be prepared by suspending amorphous fluvastatin sodium inpropan-2-ol at room temperature for a period of time sufficient toeffect the conversion to Form XLV, which typically requires about 25 h.Form XLV can then be separated from propan-2-ol by conventional meanssuch as filtering, decanting, centrifuging and the like. Preferably, theliquids are separated by vacuum filtration under an inert gas likenitrogen. After optionally washing with for example propan-2-ol, thecrystals can be dried. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XLVI

Fluvastatin sodium Form XLVI produces a PXRD pattern (FIG. 66) havingcharacteristic peaks at 3.3, 3.5, 10.2, 11.2 and 21.1±0.2 degreestwo-theta, and other peaks at 9.7, 12.1, 17.2 and 19.0±0.2 degreestwo-theta.

Form XLVI can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The ester is dissolved ina solution of about one molar equivalent of sodium in ethanol. Thesodium can be conveniently provided by dissolving the appropriatequantity of sodium hydroxide pellets in water, while exercising cautionsince the dissolution in water is highly exothermic. The solution isheated for a sufficient period of time to hydrolyze the ester, typicallyseveral hours. Then, a large excess (e.g. 10× v/v) of acetonitrile isadded to the solution to induce precipitation of Form XLVI. Theresulting slurry is then cooled to ambient temperature and Form XLVI isseparated from the ethanol and acetonitrile by conventional means suchas filtering, decanting, centrifuging and the like. Preferably, theliquids are separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Crystal Form XLVII

Fluvastatin sodium Form XLVII produces a PXRD (FIG. 67) pattern havingcharacteristic peaks at 3.3, 10.2 and 18.0±0.2 degrees two-theta, andother peaks at 8.3, 10.8, 13.6, 20.7 and 21.3±0.2 degrees two-theta.

Fluvastatin sodium Form XLVII can be prepared by exposing fluvastatinsodium Form XVIII to water vapor. Preferably, Form XVIII is maintainedunder an atmosphere of 80% relative humidity at ambient temperature.Substantially complete conversion is achieved over a period of weeks,typically about three and a half weeks.

Fluvastatin Sodium Crystal Form XLVIII

Fluvastatin sodium Form XLVIII produces a PXRD pattern havingcharacteristic peaks at 4.5, 6.7, 7.0, 10.9, 19.1, 21.7±0.2 degreestwo-theta, and other peaks at 8.9, 12.9, 13.1, 13.5, 15.2, 16.8, 17.6,18.3, 19.7, 20.6±0.2 degrees two-theta. The water content of this samplemeasured by Karl Fisher is about 6-8% by weight. The weight loss by TGAis about 8% by weight. Fluvastatin sodium Form XLII is a dihydrate.

Fluvastatin sodium Form XLVIII can be made by dissolving a lower alkylester of fluvastatin in a solution containing about one molar equivalentof sodium hydroxide in methanol. Once a homogeneous solution offluvastatin sodium is obtained, precipitation of the sodium salt isinduced by addition of acetonitrile. Formation of the salt and theaddition of acetonitrile are preferably conducted at elevatedtemperature. After cooling and being allowed to stand for a sufficienttime for crystallization to go substantially to completion, Form XLIIIcan then be separated from the methanol and acetonitrile by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the liquids are separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvatastin sodium Form XLVIII can also be prepared from fluvastatinsodium Form B. Fluvastatin sodium Form B is slurried in methanol atelevated temperature for a period of time sufficient to effect theconversion to Form XLVIII. The slurry is then cooled to ambienttemperature and Form XLVIII is separated by conventional means known toone of skill in the art such as filtering, decanting, centrifuging, andthe like. Preferably, the liquids are separated by vacuum filtrationunder an inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

In another process for preparing fluvastatin sodium Form XLVIII,fluvastatin sodium Form B is dissolved in methanol at room temperatureand the solution is heated to reflux temperature to obtain aprecipitate. The methanol stays in solution for a short amount of time.The resulting slurry is cooled and stirred at room temperature and FormXLVIII is separated by conventional means known to one of skill in theart such as filtering, decanting, centrifuging, and the like.Preferably, the liquids are separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

In another process for preparing fluvastatin sodium Form XLVIII,fluvastatin diol is completely dissolved in methanol at refluxtemperature and the solution is filtered to obtain a clear solution andheated to reflux again. Solid NaOH is added to the solution at refluxtemperature to obtain a precipitate. The resulting slurry is cooled toroom temperature to obtain a mixture having a paste-like consistency.Acetone is added dropwise to the mixture at room temperature. Thesolution is stirred at room temperature to obtain Form XLVIII as aprecipitate. Form XLVIII is separated by conventional means known to oneof skill in the art such as filtering, decanting, centrifuging, and thelike. Preferably, the liquids are separated by vacuum filtration underan inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form XLIX

Fluvastatin sodium Form XLIX produces a PXRD pattern (FIG. 69) havingcharacteristic peaks at 3.5, 5.0, 12.1, 13.5 and 20.2±0.2 degreestwo-theta and other peaks at 6.3, 10.1 and 17.1±0.2 degrees two-theta.

Form XLIX can be prepared from fluvastatin sodium Form B. According to apreferred process, about 1:8 (w/v) of Form B is dissolved in methanol atambient temperature. After dissolution, the solution is heated to refluxand then MTBE is slowly added (dropwise on a bench scale) to therefluxing solution. The addition causes fluvastatin Form XLIX toprecipitate from solution. After precipitation, the suspension can becooled to ambient temperature and Form XLIX can be separated from themethanol and MTBE by conventional means known to one of skill in the artsuch as filtering, decanting, centrifuging, and the like. Preferably,the liquids are separated by vacuum filtration under an inert gas likenitrogen. After optional washing, for example with MTBE, the crystalscan be dried. A suitable condition for drying the separated product is50EC under vacuum.

Fluvastatin Sodium Crystal Form L

Fluvastatin sodium Form L (50) produces a PXRD pattern (FIG. 70) havingcharacteristic peaks at 6.48, 6.92, 9.72, 12.64, 21.49±0.2 degreestwo-theta and other peaks at 4.53, 12.06, 13.50, 14.79, 15.79, 16.32,19.15, 23.19±0.2 degrees two-theta. The water content of this samplemeasured by Karl Fisher is about 5-6% by weight. The weight loss by TGAis about 7% by weight. Fluvastatin sodium Form L is a sesquihydrate.

Fluvastatin sodium Form L can be prepared by precipitation from amixture of methanol and ethyl acetate. The fluvastatin sodium startingmaterial, in any crystalline form or amorphous, should first bedissolved in the methanol. One gram of fluvastatin sodium will dissolvein 7 ml of methanol or more at room temperature. The starting materialcan be dissolved either at ambient or elevated temperature, e.g. theboiling point of methanol. Once dissolved, precipitation of Form L isinduced by dropwise addition of ethyl acetate to the solution atelevated temperature. The amount of ethyl acetate used is preferablyabout three times the volume of methanol. Once precipitation hasstarted, the mixture can then be allowed to cool and after an optionalperiod of time for further crystallization at ambient temperature, FormL can be separated from the methanol and ethyl acetate by conventionalmeans such as such as filtering, decanting, centrifuging and the like.Preferably, the liquids are separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LI

Fluvastatin sodium Form XLIX produces a PXRD pattern (FIG. 71) havingcharacteristic peaks at 6.2, 10.8, 14.5 and 20.7±0.2 degrees two-thetaand other peaks at 8.9, 11.5 and 23.1±0.2 degrees two-theta.

Form LI can be prepared from fluvastatin sodium Form B by a procedureanalogous to the one used to prepare Form XLIX, but substitutingacetonitrile for MTBE.

Fluvastatin Sodium Crystal Form LIII

Fluvastatin sodium Form XLIX produces a PXRD pattern (FIG. 72) havingcharacteristic peaks at 5.6, 6.3, 10.5, 20.9±0.2 degrees two-theta andother peaks at 14.3, 15.1, 15.6 and 17.1±0.2 degrees two-theta.

Form LIII can be prepared from fluvastatin sodium Form B by a procedureanalogous to the one used to prepare Form XLIX, but substituting ethylacetate for MTBE.

Fluvastatin Sodium Crystal Form LIV

Fluvastatin sodium Form LIV produces a PXRD pattern (FIG. 73) havingcharacteristic peaks at 3.4, 10.4, 18.2, 19.6, 21.3±0.2 degreestwo-theta and other peaks at 6.9, 12.1, 13.8, 17.7, 19.0±0.2 degreestwo-theta. The water content of a sample of Form LIV measured by KarlFisher was about 11% by weight. The weight loss by TGA is about 11% byweight. Fluvastatin sodium Form LIV is a trihydrate.

Fluvastatin sodium Form LIV can be prepared from by mixing fluvastatinin an aqueous solution of sodium hydroxide to obtain a suspension havinga mud-like consistency. The suspension is stirred at room temperatureand the product can be separated by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the liquidsare separated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LV

Fluvastatin sodium Form LV produces a PXRD pattern having characteristicpeaks at 3.7, 5.0, 5.9, 12.2±0.2 degrees two-theta and other peaks at5.6, 8.7, 10.1, 11.2±0.2 degrees two-theta. The water content of thissample measured by Karl Fisher is about 7% by weight. The weight loss byTGA is about 7% by weight. Fluvastatin sodium Form LV is a dihydrate.

Fluvastatin sodium Form LV can be prepared by precipitation from amixture of methanol and acetonitrile. Preferred mixtures contain fromabout 10% to about 12%, more preferably about 12.5% by volume (methanolvolume/acetonitrile volume X 100).

A preferred procedure starts with a lower alkyl ester of fluvastatin.The fluvastatin ester is added to acetonitrile and the mixture is heateduntil the ester dissolves. The solution is then cooled and a solution ofsodium hydroxide in methanol is added to it. Form LV can be separatedfrom the methanol and acetonitrile by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the liquidsare separated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LVI

Fluvastatin sodium Form LVI produces a PXRD pattern (FIG. 75) havingcharacteristic peaks at 3.4, 22.1 and 27.4±0.2 degrees two-theta andother peaks at 6.8, 10.2, 13.6, 18.5 and 20.0±0.2 degrees two-theta.

Form LVI can be prepared directly from a lower alkyl ester derivative offluvastatin having a ketal protecting group on the ∃ and * hydroxylgroups, such as an acetonide protected fluvastatin methyl ester. Thestarting material is taken up in THF and the acetonide is hydrolyzedwith HCl, preferably 1.5% (aq.) HCl. The time required will be dependentupon the concentration of the starting material and acid concentrationused, but can be readily determined by reaction-monitoring techniquessuch as thin layer chromatography. Thereafter, a sufficient excess ofNaOH is added to neutralize the HCl. The THF is then evaporated and theresidue is taken up in acetone. About a molar equivalent of sodiumhydroxide is added to the solution. Over time, fluvastatin sodiumprecipitates as Form LVI. Form LVI can be separated by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the acetone is separated by vacuum filtration under an inertgas like nitrogen. After optional washing, for example with acetone, thecrystals can be dried. A suitable condition for drying is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LVII

Fluvastatin sodium Form LVII produces a PXRD pattern (FIG. 76) havingcharacteristic peaks at 3.7, 5.0, 5.5, 10.1,12.1±0.2 degrees two-thetaand other peaks at 8.6, 11.1, 14.9, 21.7, 22.8±0.2 degrees two-theta.The water content of this sample measured by Karl Fisher is about 2% byweight. The weight loss by TGA is about 2% by weight. Fluvastatin sodiumForm LVII is a hemihydrate.

Fluvastatin sodium Form LVII can be prepared by forming a heterogeneousmixture of fluvastatin sodium Form VII and ethanol and maintaining theheterogeneous mixture until substantially all of the Form VII isconverted into Form LVII. Preferably, the ethanol is anhydrous(“absolute”) and the suspension is maintained under dry conditions. FormLVII can be separated from the ethanol by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the ethanolseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LVIII

Fluvastatin sodium Form LVIII produces a PXRD pattern (FIG. 77) havingcharacteristic peaks at 3.4, 3.8, 5.4, 5.7, 10.3±0.2 degrees two-thetaand other peaks at 4.7, 7.2, 8.4, 11.5, 17.5, 20.4, 21.4, 23.1±0.2degrees two-theta. The water content of this sample measured by KarlFisher is about 4-5% by weight. The weight loss by TGA is about 6-7% byweight.

Fluvastatin sodium Form LVIII can be prepared by forming a heterogeneousmixture of fluvastatin sodium and propan-2-ol and maintaining theheterogeneous mixture for a period of time sufficient to substantiallyconvert the fluvastatin sodium into Form LVIII. A preferred startingmaterial is fluvastatin sodium Form B. The conversion can be acceleratedby heating the suspension, preferably to reflux temperature of thediluent. Form LVIII can be separated from the propan-2-ol byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the liquids are separated by vacuum filtration underan inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LX

Fluvastatin sodium Form LX produces a PXRD pattern (FIG. 78) havingcharacteristic peaks at 5.6, 6.3 and 10.5±0.2 degrees two-theta andother peaks at 4.1, 5.0, 11.0, 15.7, 17.2 and 19.6±0.2 degreestwo-theta. Form LX may be prepared by adding ethyl acetate to solutionof fluvastatin sodium in methanol. In the exemplified embodiment, thesolution is heated, followed by portion-wise addition of ethyl acetate.Form LX then precipitates, and is stirred and recovered by conventionaltechniques.

Fluvastatin Sodium Crystal Form LXIV

Fluvastatin sodium Form LXIV produces a PXRD pattern (FIG. 79) havingcharacteristic peaks at 5.8, 13.9 and 14.7±0.2 degrees two-theta andother peaks at 5.1, 9.3, 11.7 and 19.4±0.2 degrees two-theta.

Form LXIV can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. Two different processeshave been discovered. According to a preferred embodiment of oneprocess, about 0.1:1 (w/v) of the starting material is dissolved inmethanol while heating the mixture to reflux. About one equivalent ofsodium hydroxide is then added to the refluxing solution. Duringhydrolysis, fluvastatin sodium begins to precipitate. After thehydrolysis is complete, which can be determined by thin layerchromatography, the slurry is cooled to ambient temperature. Coolingcauses the precipitate to redissolve. Acetone is then added to thesolution to reprecipitate fluvastatin sodium in Form LXIV. ThereafterForm LXIV can be separated from the methanol and acetone by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the liquids are separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

According to an alternative process for making Form LXIV, about 1:15(w/v) of the starting lower alkyl ester of fluvastatin is dissolved inacetone. Then an excess of sodium hydroxide dissolved in methanol isadded to the solution. Over time, fluvastatin sodium precipitates fromthe solution as Form LXIV. Form LXIV can be separated from the acetoneand methanol by conventional techniques such as filtering, decanting,centrifuging and the like, preferably filtering under an inertatmosphere like nitrogen. After optional washing, for example withacetone, the separated Form LXIV may be dried. A suitable dryingcondition is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXV

Fluvastatin sodium Form LXV produces a PXRD pattern (FIG. 80) havingcharacteristic peaks at 5.8, 13.9 and 14.7±0.2 degrees two-theta andother peaks at 5.1, 9.3, 11.7 and 19.4±0.2 degrees two-theta.

Form LXV can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. According to a preferredprocess, about 1:7 (w/v) of the starting material is dissolved inmethanol containing about one equivalent of sodium at ambienttemperature. After the mixture becomes clear, about six volumes ofpropan-2-ol is added to induce precipitation of fluvastatin sodium inForm LXV. Thereafter Form LXV can be separated from the methanol andpropan-2-ol by conventional means such as filtering, decanting,centrifuging and the like. Preferably, the liquids are separated byvacuum filtration under an inert gas like nitrogen. After optionalwashing, for example with acetone, the crystals can be dried. A suitablecondition for drying the separated product is 50EC under vacuum. In theprocess, five volumes of acetone can be substituted for the six volumesof propan-2-ol.

Fluvastatin Sodium Crystal Form LXVI

Fluvastatin sodium Form LXVI produces a PXRD pattern (FIG. 81) havingcharacteristic peaks at 3.6, 10.8, 17.8, 18.3 and 21.6±0.2 degreestwo-theta and other peaks at 7.2, 12.2, 14.4 and 25.5±0.2 degreestwo-theta.

We have been able to produce Form LXVI from several other crystal formsof fluvastatin sodium by similar processes. In general terms eitherfluvastatin sodium Form VI, B or XV is dissolved in water either atambient temperature or elevated temperature to obtain a clear solution.The solution is refluxed, preferably for one to two hours and then iscooled or allowed to cool to ambient temperature. After a period oftime, Form LXVI precipitates from the solution. Form LXVI can beseparated from the water by conventional means such as by filtering,decanting, centrifuging and the like. Preferably, the water is separatedby vacuum filtration under an inert gas like nitrogen. After optionalwashing, for example with water, the crystals can be dried. A suitablecondition for drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXVII

Fluvastatin sodium Form LXVII produces a PXRD pattern (FIG. 82) havingcharacteristic peaks at 3.7 and 4.4±0.2 degrees two-theta and otherpeaks at 5.6 and 10.8±0.2 degrees two-theta.

Form LXVII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. According to a preferredprocess, 1:15 (w/v) of the starting material is dissolved in acetone. Anexcess of sodium hydroxide in methanol is added and the mixture ismaintained at ambient temperature until hydrolysis of the ester iscomplete. Thereafter, fluvastatin sodium precipitates in Form LXVII.Thereafter Form LXVII can be separated from the methanol and acetone byconventional means such as by filtering, decanting, centrifuging and thelike. Preferably, the methanol and acetone is separated by vacuumfiltration under an inert gas like nitrogen. After optional washing, forexample with acetone, the crystals can be dried. A suitable conditionfor drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXVIII

Fluvastatin sodium Form LXVIII produces a PXRD pattern (FIG. 83) havingcharacteristic peaks at 3.6, 5.9, 10.8 and 11.6±0.2 degrees two-thetaand other peaks at 9.3, 15.4, 17.0, 18.4 and 23.0±0.2 degrees two-theta.

Form LXVIII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. According to a preferredprocess, 1:15 (w/v) of the starting material is dissolved in acetone. Anexcess of sodium hydroxide in methanol as added to the solution. Thesolution is maintained at ambient temperature for a period of timesufficient to hydrolyze the ester, which can be determined by thin layerchromatography. Thereafter, Form LXVIII crystallizes eitherspontaneously or with cooling and can be separated from the methanol andacetone by conventional means such as by filtering, decanting,centrifuging and the like. Preferably, the methanol and acetone areseparated by vacuum filtration under an inert gas like nitrogen. Afteroptional washing, for example with acetone, the crystals can be dried. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LXIX

Fluvastatin sodium Form LXIX produces a PXRD pattern (FIG. 84) havingcharacteristic peaks at 3.5, 5.7, 10.8, 18.2 and 21.6±0.2 degreestwo-theta and other peaks at 12.4, 14.7, 20.4, 22.4 and 25.4±0.2 degreestwo-theta.

Form LXIX can be prepared by slurrying fluvastatin sodium Form VI inpropan-2-ol at reflux temperature for a period of time sufficient toeffect the conversion. After cooling the solution, Form LXIX can beseparated from the propan-2-ol by conventional means such as filtering,decanting, centrifuging and the like. Preferably, the propan-2-ol isseparated by vacuum filtration under an inert gas like nitrogen. Afteroptional washing, for example with propan-2-ol, the crystals can bedried. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Crystal Form LXX

Fluvastatin sodium Form LXX produces a PXRD pattern (FIG. 85) havingcharacteristic peaks at 3.0, 3.4, 5.9, and 13.8±0.2 degrees two-thetaand other peaks at 8.2, 8.9, 18.6, 21.1 and 22.4±0.2 degrees two-theta.

Form LXX can be prepared from fluvastatin sodium such as Form LXVII bydissolving in water at reflux temperature and adding a ten fold excessof acetone to induce precipitation of fluvastatin sodium in Form LXX.After cooling the resulting mixture to ambient temperature, Form LXX canbe separated from the water and acetone by conventional means such as byfiltering, decanting, centrifuging and the like. Preferably, the waterand acetone are separated by vacuum filtration under an inert gas likenitrogen. After optional washing, for example with acetone, the crystalscan be dried. A suitable condition for drying the separated product is50EC under vacuum.

Fluvastatin Sodium Crystal Form LXXI

Fluvastatin sodium Form LXXI produces a PXRD pattern (FIG. 86) havingcharacteristic peaks at 3.9, 7.8, 11.6 and 15.5±0.2 degrees two-thetaand other peaks at 9.2, 13.3, 19.0 and 23.2±0.2 degrees two-theta.

Form LXXI can be prepared by refluxing a 1:1 (w/v) mixture offluvastatin sodium Form LXVII and water and then adding a large excessof acetone and maintaining the mixture for a period of time sufficientto effect the conversion to Form LXXI. After cooling the resultingmixture to ambient temperature, Form LXXI can be separated from thewater and acetone by conventional means such as by filtering, decanting,centrifuging and the like. Preferably, the water and acetone areseparated by vacuum filtration under an inert gas like nitrogen. Afteroptional washing, for example with acetone, the crystals can be dried. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LXXII

Fluvastatin sodium Form LXXII produces a PXRD pattern (FIG. 87) havingcharacteristic peaks at 3.7, 5.7 and 12.1±0.2 degrees two-theta andother peaks at 5.0, 10.8, 16.8 and 20.1±0.2 degrees two-theta.

Form LXXII can be prepared from fluvastatin sodium Form VI. According toone preferred procedure, the starting material is suspended in an about40:1 mixture of acetone and water and heated to reflux for a period oftime sufficient to effect the conversion to Form LXXII. After themixture has cooled to ambient temperature, Form LXXII can be separatedfrom the water and acetone by conventional means such as by filtering,decanting, centrifuging and the like. Preferably, the water and acetoneare separated by vacuum filtration under an inert gas like nitrogen.After optional washing, for example with acetone, the crystals can bedried. A suitable condition for drying the separated product is 50ECunder vacuum.

According to another preferred procedure, Form VI is suspended inacetonitrile and heated to reflux for a period of time sufficient toeffect the conversion. After the mixture has cooled to ambienttemperature, Form LXXII can be separated from the acetonitrile byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the acetonitrile is separated by vacuum filtrationunder an inert gas like nitrogen. After optional washing, for examplewith acetonitrile, the crystals can be dried. A suitable condition fordrying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXXIV

Fluvastatin sodium Form LXXIV produces a PXRD pattern (FIG. 89) havingcharacteristic peaks at 4.0, 12.8, 19.0, 19.9 and 25.8±0.2 degreestwo-theta and other peaks at 5.4, 11.8, 13.4, 18.0 and 24.6±0.2 degreestwo-theta.

Form LXXIV can be prepared from fluvastatin sodium Form B by suspendingForm B in a refluxing about 10:1 mixture of propan-2-ol and water for asufficient period to effect the conversion. After cooling the solution,Form LXXIV can be separated from the propan-2-ol and water byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the propan-2-ol and water are separated by vacuumfiltration under an inert gas like nitrogen. After optional washing, forexample with propan-2-ol, the crystals can be dried. A suitablecondition for drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXXV

Fluvastatin sodium Form LXXV produces a PXRD pattern (FIG. 90) havingcharacteristic peaks at 4.4, 6.6, 10.8, 14.3 and 22.2±0.2 degreestwo-theta and other peaks at 7.8, 15.0, 19.8, 20.4 and 21.4±0.2 degreestwo-theta.

Form LXXV can be prepared from fluvastatin sodium Form XXX by refluxingForm XXX in methanol for a period of time sufficient to effect theconversion. After cooling the solution, Form LXXV can be separated fromthe methanol by conventional means such as filtering, decanting,centrifuging and the like. Preferably, the methanol is separated byvacuum filtration under an inert gas like nitrogen. After optionalwashing, for example with methanol, the crystals can be dried. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Crystal Form LXXVI

Fluvastatin sodium Form LXXVI produces a PXRD pattern (FIG. 91) havingcharacteristic peaks at 3.5, 7.0, 10.5 and 13.0 ±0.2 degrees two-theta.

LXXVI can be prepared directly from a lower alkyl ester of fluvastatinsuch as fluvastatin methyl ester. According to a preferred process, thestarting material is dissolved in an about 5:3 ethanol:water mixturecontaining about one equivalent of sodium hydroxide. After thehydrolysis is complete, the mixture is partially concentrated andadditional water is added. The mixture is then extracted with a waterimmiscible solvent such as ethyl acetate. The aqueous phase is thendistilled off leaving a residue that is fluvastatin sodium Form LXXVI.

Fluvastatin Sodium Crystal Form LXXVII

Fluvastatin sodium Form LXXVII produces a PXRD pattern (FIG. 92) havingcharacteristic peaks at 3.6, 8.8, 11.0, 12.8 and 17.8±0.2 degreestwo-theta and other peaks at 7.3, 20.2 and 31.0±0.2 degrees two-theta.

Form LXXVII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. According to a preferredprocess, 1:30 (w/v) of the starting material is dissolved in ethylacetate. An excess of sodium hydroxide in water is added to thesolution. The solution is maintained at ambient temperature for a periodof time sufficient to hydrolyze the ester, which can be determined bythin layer chromatography. Thereafter, Form LXXVII crystallizes and canbe separated from the ethyl acetate and water by conventional means suchas filtering, decanting, centrifuging and the like. Preferably, theethyl acetate and water are separated by vacuum filtration under aninert gas like nitrogen. After optional washing, for example with ethylacetate, the crystals can be dried. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Crystal Form LXXVIII

Fluvastatin sodium Form LXXVIII produces a PXRD pattern (FIG. 93) havingcharacteristic peaks at 8.8, 19.1, 27.2, 29.6 and 30.9±0.2 degreestwo-theta and other peaks at 3.4, 11.3, 17.7, 22.5 and 32.2±0.2 degreestwo-theta.

Form LXXVIII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The starting material ishydrolyzed with sodium hydroxide in water. Then, the reaction mixture isextracted with ethyl acetate. The aqueous phase is concentrated. Theresidue is then contacted with either propan-2-ol or acetonitrile forone or two days. After conventional separation of the propan-2-ol oracetonitrile, the fluvastatin sodium is in Form LXXVIII. After optionalwashing, for example with acetonitrile, the crystals can be dried. Asuitable condition for drying the separated product is 50EC undervacuum.

Summary of Distinctive Physical Properties of Fluvastatin Sodium CrystalForms

A summary of the water content of Forms IV, IV-1, VI, VII, XI, XI-2,XVI-XVIII, XIX, XIX-1, XX, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVII,XXXVIII, XLI, XLII, XLIII, XLVIII, L, LIV, LV, LIV, LV, LVII, and LVIIIis provided in the table below.

Water Form Water Content Weight Loss Content Hydration IV 4% KF 8.3% TGA4 — IV-1 2.1-2.6% KF 10.5% TGA 2-3 — VI 5.0-5.6% KF 12% TGA    5-6% —VII 4.1%-4.5% KF 13-14% TGA + 1-9 — hygroscopicity XI 4-6% KF 6-8% TGA +1-6 — hygroscopicity XI-2 1.9-3.2% KF 7.7% TGA 2-3 — XVI 3-4% KF 8.7%TGA 3-4 — XVII 8.4% TGA 8 — XVIII 4% KF 4% TGA 4 monohydrate XIX 19-28%KF 22-26% TGA 19-28 Hexahydrate 8-hydrate 9-hydrate XIX-1 8% KF 7% TGADihydrate XX 19% KF 19% TGA 19  hexahydrate XXIX — — — XXX 4% KF 10% TGA— XXXI 16% KF 16% TGA Tetrahydrate XXXIII 7% KF 7% TGA Dihydrate 9.5% KF10.7% TGA hemipenta- hydrate XXXIV 10% KF 20.1% TGA — XXXV 15% KF 31%TGA — XXXVII 9% KF 9% TGA Hemipenta- hydrate XXXVIII 6-7% KF 10-11% TGA— XLI 9% KF 9% TGA monohydrate XLII 4% KF 5% TGA monohydrate XLIII 9-11%KF 12% TGA — XLIV 4-6% KF 8-10% TGA — XLVIII 6-8% KF 8% TGA Dihydrate L5-6% KF 7% TGA Sesqui- hydrate LIV 11% KF 11% TGA Trihydrate LV 7% KF 7%TGA Dihydrate LVII 2% KF 2% TGA hemihydrate LVIII 4.6% KF 6.4% TGA —

In addition to the crystalline polymorphic forms of fluvastatin sodiumpreviously described, we have discovered a number of semi-crystallinesolid forms of fluvastatin that can be reproducibly obtained byfollowing certain procedures set forth below.

Fluvastatin Sodium Form XC

Fluvastatin sodium Form XC produces a PXRD pattern (FIG. 97) havingcharacteristic peaks at 3.2 and 9.6±0.2 degrees two-theta and otherpeaks at 11.8 and 19.8±0.2 degrees two-theta.

Fluvastatin sodium Form XC can be prepared from fluvastatin sodium FormB by dissolving it in ethanol at ambient temperature and then addingcyclohexane to induce precipitation. Afterwards, Form XC can beseparated from the ethanol and cyclohexane by conventional means such asby filtering, decanting, centrifuging and the like. Preferably, theliquids are separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Form XCI

Fluvastatin sodium Form XCI produces a PXRD pattern (FIG. 98) havingcharacteristic peaks at 4.7, 5.6 and 13.8±0.2 degrees two-theta andother peaks at 7.3, 9.6, 10.8, 16.4, 17.6, 19.8, 20.8 and 23.1±0.2degrees two-theta.

Fluvastatin sodium Form XCI can be prepared from fluvastatin sodium FormXV by suspending Form XV in ethyl acetate and maintaining the suspensionat elevated temperature for a sufficient period of time to convert FormXV into Form XCI. After cooling the suspension to ambient temperature,Form XCI can be separated from the ethyl acetate by conventional meanssuch as filtering, decanting, centrifuging and the like. Preferably, theethyl acetate is separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Form XCII

Fluvastatin sodium Form XCII produces a PXRD pattern (FIG. 99) havingcharacteristic peaks at 3.4, 10.1 and 11.8±0.2 degrees two-theta andother peaks at 4.1, 17.8, 20.1, 21.7, 23.4 and 25.3±0.2 degreestwo-theta.

Fluvastatin sodium Form XCII can be prepared from fluvastatin sodiumForm B by dissolving it in a 10:1 ethanol:methanol at reflux temperatureand then adding hexanes to induce precipitation. Afterwards, Form XCIIcan be separated from the ethanol, methanol and cyclohexane byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the liquids are separated by vacuum filtration underan inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Form XCIII

Fluvastatin sodium Form XCIII produces a PXRD pattern (FIG. 100) havingcharacteristic peaks at 4.9, 5.9, 7.2 and 12.3±0.2 degrees two-theta andother peaks at 9.7, 10.9 and 13.9±0.2 degrees two-theta.

Fluvastatin sodium Form XCIII can be prepared from fluvastatin sodiumForm XV by suspending it in propan-1-ol at ambient temperature andmaintaining the suspension at ambient temperature for a sufficientperiod of time to convert Form XV into Form XCIII. Form XCIII can beseparated from the propan-1-ol by conventional means such as filtering,decanting, centrifuging and the like. Preferably, the propan-1-ol isseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Form XCIV

Fluvastatin sodium Form XCIV produces a PXRD pattern (FIG. 101) havingcharacteristic peaks at 4.6, 9.2 and 20.3±0.2 degrees two-theta andother peaks at 4.1, 6.7, 13.0, 15.8, 17.7, 21.7 and 23.0±0.2 degreestwo-theta.

Fluvastatin sodium Form XCIV can be prepared from fluvastatin sodiumForm XV by suspending it in butan-1-ol at ambient temperature andmaintaining the suspension at ambient temperature for a sufficientperiod to convert Form XV into Form XCIII. Form XCIII can be separatedfrom the butan-1-ol by conventional means such as by filtering,decanting, centrifuging and the like. Preferably, the butan-l-ol isseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Form XCV

Fluvastatin sodium Form XCV produces a PXRD pattern (FIG. 102) havingcharacteristic peaks at 5.7, 13.0, 19.8 and 20.5±0.2 degrees two-thetaand other peaks at 4.2, 4.7, 12.3 and 15.9±0.2 degrees two-theta.

Fluvastatin sodium Form XCV can be prepared from fluvastatin sodium FormXV by suspending it in either ethyl acetate, acetone, 1,4-dioxane or MEKat ambient temperature and maintaining the suspension at ambienttemperature for a sufficient period of time to convert Form XV into FormXCV. Form XCV can be separated from the diluent by conventional meanssuch as filtering, decanting, centrifuging and the like. Preferably, thediluent is separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Fluvastatin Sodium Form XCVI

Fluvastatin sodium Form XCVI produces a PXRD pattern (FIG. 103) havingcharacteristic peaks at 3.7, 11.0, 12.9 and 18.2±0.2 degrees two-thetaand other peaks at 5.2, 8.3, 17.7, 21.5 and 25.5±0.2 degrees two-theta.

Fluvastatin sodium Form XCVI can be prepared from fluvastatin sodiumForm XV by suspending it in THF at ambient temperature and maintainingthe suspension at ambient temperature for a sufficient period of time toconvert Form XV into Form XCVI. Form XCV can be separated from the THFby conventional means such as filtering, decanting, centrifuging and thelike. Preferably, the THF is separated by vacuum filtration under aninert gas like nitrogen. A suitable condition for drying the separatedproduct is 50EC under vacuum.

Fluvastatin Sodium Form XCVII

Fluvastatin sodium Form XCVII produces a PXRD pattern (FIG. 104) havinga characteristic peak at 3.5±0.2 degrees two-theta and other peaks at9.4, 18.4, 20.0, 21.2 and 22.0±0.2 degrees two-theta.

Form XCVII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The starting material ishydrolyzed with sodium hydroxide in cyclohexane. According to apreferred procedure, the sodium hydroxide is added as a methanolicsolution. Over time, fluvastatin sodium Form XCVII precipitates from themixture. Form XCVII can be separated from the cyclohexane byconventional means such as filtering, decanting, centrifuging and thelike. Preferably, the cyclohexane is separated by vacuum filtrationunder an inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Form XCVIII

Fluvastatin sodium Form XCVIII produces a PXRD pattern (FIG. 105) havingcharacteristic peaks at 3.8 and 10.8±0.2 degrees two-theta and otherpeaks at 6.4 and 14.4±0.2 degrees two-theta.

Form XCVIII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The starting material ishydrolyzed with sodium hydroxide in a concentrated methanol solution atelevated temperature. After completion of the hydrolysis, a large excessof acetonitrile (e.g. ˜7×) is added to the methanol at elevatedtemperature. The hot solution is then cooled or allowed to cool toambient temperature and held until Form XCVIII precipitates from thesolution. Form XCVIII can be separated from the methanol andacetonitrile by conventional means such as by filtering, decanting,centrifuging and the like. Preferably, the methanol and acetonitrile areseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Form XCIX

Fluvastatin sodium Form XCIX produces a PXRD pattern (FIG. 106) havingcharacteristic peaks at 3.6, 5.3, 8.7 and 10.4±0.2 degrees two-theta andother peaks at 17.9 and 21.5±0.2 degrees two-theta.

Fluvastatin sodium Form XCIX can be prepared from fluvastatin sodiumForm VI by suspending it in ethanol at ambient temperature andmaintaining the suspension at ambient temperature for a sufficientperiod to convert Form VI into Form XCIX. Form XCIX can be separatedfrom the ethanol by conventional means such as filtering, decanting,centrifuging and the like. Preferably, the ethanol is separated byvacuum filtration under an inert gas like nitrogen. A suitable conditionfor drying the separated product is 50EC under vacuum.

Fluvastatin Sodium Form C

Fluvastatin sodium Form C (100) produces a PXRD pattern (FIG. 107)having characteristic peaks at 3.3, 9.8, 11.0, 19.0 and 22.7±0.2 degreestwo-theta and other peaks at 6.2, 17.2 and 21.3±0.2 degrees two-theta.

Form C can be prepared directly from a lower alkyl ester of fluvastatinsuch as fluvastatin methyl ester. The starting material is hydrolyzedwith sodium hydroxide in dichloromethane at room temperature. Over time,fluvastatin sodium precipitates from the reaction mixture as Form C.Form C can be separated from the dichloromethane by conventional meanssuch as filtering, decanting, centrifuging and the like. Preferably, thedichloromethane is separated by vacuum filtration under an inert gaslike nitrogen. A suitable condition for drying the separated product is50EC under vacuum.

Fluvastatin Sodium Form CI

Fluvastatin sodium Form CI produces a PXRD pattern (FIG. 108) havingcharacteristic peaks at 4.5 and 11.2±0.2 degrees two-theta and otherpeaks at 5.7 and 19.3±0.2 degrees two-theta.

Form CI can be prepared directly from a lower alkyl ester of fluvastatinsuch as fluvastatin methyl ester. The starting material is hydrolyzedwith sodium hydroxide in a mixture of acetone and methanol. Aftercompletion of the hydrolysis and, where applicable, cooling to ambienttemperature, Form CI precipitates from the reaction mixture. Form CI canbe separated from the methanol and acetone by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, themethanol and acetone are separated by vacuum filtration under an inertgas like nitrogen. A suitable condition for drying the separated productis 50EC under vacuum.

Fluvastatin Sodium Form CII

Fluvastatin sodium Form CII produces a PXRD pattern (FIG. 109) having acharacteristic peak at 4.3±0.2 degrees two-theta and other peaks at 8.7,11.0 and 19.2±0.2 degrees two-theta.

Form CII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The starting material ishydrolyzed with sodium hydroxide in a mixture of acetone and methanol.After completion of the hydrolysis and, where applicable, cooling toambient temperature, Form CI precipitates from the reaction mixture.Form CII can be separated from the methanol and acetone by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the methanol and acetone are separated by vacuum filtrationunder an inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Form CIII

Fluvastatin sodium Form CIII produces a PXRD pattern (FIG. 110) havingcharacteristic peaks at 4.5, 20.4, 25.9 and 30.6±0.2 degrees two-thetaand other peaks at 5.6, 10.1, 12.5, 19.0 and 19.7±0.2 degrees two-theta.

Form CIII can be prepared directly from a lower alkyl ester offluvastatin such as fluvastatin methyl ester. The starting material ishydrolyzed with sodium hydroxide in a mixture of acetone and water.After completion of the hydrolysis and, where applicable, cooling toambient temperature, Form CIII precipitates from the reaction mixture.Form CIII can be separated from the water and acetone by conventionalmeans such as filtering, decanting, centrifuging and the like.Preferably, the water and acetone are separated by vacuum filtrationunder an inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Fluvastatin Sodium Form CIV

Fluvastatin sodium Form CIV produces a PXRD pattern (FIG. 111) havingcharacteristic peaks at 3.7, 9.7, 18.3, 19.9, 21.8±0.2 degrees two-thetaand other peaks at 5.6, 11.3, 14.8, 22.6±0.2 degrees two-theta. Form CIVcan be prepared directly from a lower alkyl ester of fluvastatin such asfluvastatin methyl ester. The starting material is hydrolyzed withsodium hydroxide in THF. After completion of the hydrolysis, hexanes isadded to the reaction mixture to induce precipitation of Form CIV. FormCIV can be separated from the THF by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the THF isseparated by vacuum filtration under an inert gas like nitrogen. Asuitable condition for drying the separated product is 50EC undervacuum.

Fluvastatin Sodium Form CV

Fluvastatin sodium Form CV produces a PXRD pattern (FIG. 112) havingcharacteristic peaks at 3.7, 8.9, 19.1, 22.5, 29.7±0.2 degrees two-thetaand other peaks at 11.5, 17.0, 25.1, 26.9, 28.2±0.2 degrees two-theta.Form CV can be prepared directly from a lower alkyl ester of fluvastatinsuch as fluvastatin methyl ester. The starting material is hydrolyzedwith sodium hydroxide in acetonitrile at elevated temperature. Aftercompletion of the hydrolysis, the reaction mixture is cooled or allowedto cool. Over time, fluvastatin sodium precipitates as Form CV. Form CVcan be separated from the acetonitrile by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, theacetonitrile is separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Process for Preparing Amorphous Fluvastatin Sodium

We have discovered that fluvastatin sodium precipitates in an amorphousstate from 1,4-dioxane and cyclohexane. Accordingly, one preferredprocess for making amorphous fluvastatin sodium of the present inventionis to dissolve fluvastatin sodium in 1,4-dioxane, more preferably atelevated temperature, yet more preferably at about 85EC, and cooling theresulting solution to induce precipitation of amorphous fluvastatinsodium.

In another preferred process, a lower alkyl ester of fluvastatin issuspended in cyclohexane. Then, about one molar equivalent of sodiumhydroxide dissolved in a minimum of protic solvent like methanol, isadded to the suspension. The addition should cause the suspension toclarify. Upon standing, fluvastatin sodium may precipitate from thesolution in amorphous form. Otherwise, additional cyclohexane can beadded to induce precipitation.

In each of the foregoing processes, the precipitate is then separatedfrom the 1,4-dioxane or cyclohexane by conventional means such asfiltering, decanting, centrifuging and the like. Preferably, the1,4-dioxane is separated by vacuum filtration under an inert gas likenitrogen. A suitable condition for drying the separated product is 50ECunder vacuum.

Pharmaceutical Compositions and Dosage Forms Containing—And Methods ofMedical Treatment Using The Novel Fluvastatin Sodium Forms

Fluvastatin exerts an antihypercholesterolemia and antihyperlipidemiaeffect in mammals, especially humans. Accordingly, fluvastatin sodiumForms I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII, XIII,XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX,XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI,XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV,LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI,LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, XCIII, XCIV,XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV and mixturesthereof with each other as well as with other crystalline forms offluvastatin sodium are useful for delivering fluvastatin to thegastrointestinal tract, bloodstream and liver of humans and othermammals suffering from or at risk of atherosclerosis. In particular,they are useful as active ingredients in pharmaceutical compositions anddosage forms. For this purpose, they may be formulated into a variety ofcompositions and dosage forms for administration to humans and animals.

Pharmaceutical compositions of the present invention contain fluvastatinsodium Form I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII,XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII,XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX,XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII,LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX,LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII,XCIII, XCIV, XCV, XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CVor mixtures thereof with each other or other crystalline forms offluvastatin sodium, optionally in mixtures with one or more other activeingredient(s). In addition to the active ingredient(s), thepharmaceutical compositions of the present invention may contain one ormore excipients. Excipients are added to the composition for a varietyof purposes.

Diluents increase the bulk of a solid pharmaceutical composition and maymake a pharmaceutical dosage form containing the composition easier forthe patient and care giver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelitinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage formlike a tablet may include excipients whose functions include helping tobind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flow properties of non-compactedsolid composition and improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by compaction of a powderedcomposition, the composition is subjected to pressure from a punch anddie. Some excipients and active ingredients have a tendency to adhere tothe surfaces of the punch and die, which can cause the product to havepitting and other surface irregularities. A lubricant can be added tothe composition to reduce adhesion and ease release of the product fromthe die. Lubricants include magnesium stearate, calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,fluvastatin sodium Form I, II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI,XI-2, XII, XIII, XVI, XVII, XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV,XXVI, XXVII, XXIX, XXX, XXXI, XXXIII, XXXIV, XXXV, XXXVI, XXXVII,XXXVIII, XXXIX, XLI, XLII, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX,L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII,LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII andany other solid excipients are dissolved or suspended in a liquidcarrier such as water, vegetable oil, alcohol, polyethylene glycol,propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

A liquid composition according to the present invention may also containa buffer such as guconic acid, lactic acid, citric acid or acetic acid,sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosage formsinclude dosage forms suitable for oral, buccal, rectal, parenteral(including subcutaneous, intramuscular, and intravenous), inhalant andophthalmic administration. Although the most suitable route in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and lozenges as well as liquid syrups,suspensions and elixirs.

An especially preferred dosage form of the present invention is acapsule containing the composition, preferably a powdered or granulatedsolid composition of the invention, within either a hard or soft shell.The shell may be made from gelatin and optionally contain a plasticizersuch as glycerin and sorbitol, and an opacifying agent or colorant. Anespecially preferred capsule filling contains, in addition to one ormore of the fluvastatin sodium crystalline forms of this invention, theexcipients magnesium stearate, microcrystalline cellulose,pregelatinized starch, sodium lauryl sulfate and talc.

Another especially preferred dosage form of this invention is acompressed tablet that contains, in addition to one or more of thefluvastatin sodium crystalline forms of this invention, the excipientsmicrocrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, potassium bicarbonate, povidone, magnesium stearate, ironoxide yellow, titanium dioxide and polyethylene glycol 8000.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filing may be prepared by wetgranulation. In wet granulation some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpup into granules. The granulate is screened and/or milled, dried andthen screened and/or milled to the desired particle size. The granulatemay then be tableted or other excipients may be added prior to tabletingsuch as a glidant and or lubricant.

A tableting composition may be prepared conventionally by dry blending.For instance, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may be compressed subsequently into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suited todirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in the particularformulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, only they are not subjected to a final tableting step.

Capsules, tablets and lozenges and other unit dosage forms preferablycontain a dosage equivalent to from about 10 to about 100 mgfluvastatin. Preferably the dosage is equivalent to from about 20 toabout 80 mg of fluvastatin. More particularly, immediate or uncontrolledrelease dosage forms preferably contain the equivalent of from abut 20to about 40 mg of fluvastatin and extended release dosage formspreferably contain the equivalent of from about 60 to about 100 mg offluvastatin, more preferably about 80 mg of fluvastatin.

Process for Preparing Fluvastatin Sodium Crystal Form B

In another aspect, the present invention provides a process forpreparing known fluvastatin Form B. In the process, the free acid offluvastatin, fluvastatin lactone or a mixture of the two, is dissolvedin a solution containing about one molar equivalent of sodium hydroxidein a mixture of water and methanol. The most preferred solvent is a 10:1mixture of methanol:water. Conversion of any lactone that may be presentin the starting material can be monitored by HPLC. Once a homogeneoussolution of fluvastatin sodium is obtained, precipitation of the sodiumsalt is induced by addition of methyl tert-butyl ether (“MTBE”).Formation of the salt and the initial addition of MTBE are preferablyconducted at elevated temperature, e.g. the reflux temperature of thesolvent system. Form B can be separated from the methanol, water andMTBE by conventional means such as filtering, decanting, centrifugingand the like. Preferably, the liquids are separated by vacuum filtrationunder an inert gas like nitrogen. A suitable condition for drying theseparated product is 50EC under vacuum.

Having thus described the present invention with reference to certainpreferred embodiments, the processes for producing fluvastatin sodium I,II, III, IV, IV-1, V, VI, VII, IX, IX-1, XI, XI-2, XII, XIII, XVI, XVII,XVIII, XIX, XIX-1, XX, XXII, XXIII, XXIV, XXVI, XXVII, XXIX, XXX, XXXI,XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLI, XLII, XLIII,XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII,LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII,LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, XC, XCI, XCII, XCIII, XCIV, XCV,XCVI, XCVII, XCVIII, XCIX, C, CI, CII, CIII, CIV, CV and B of thepresent invention and techniques suitable for identifying them arefurther illustrated by the examples which follow. These examples areprovided for illustrative purposes only and are not intended to limitthe invention in any way.

EXAMPLES General

Powder X-ray diffraction data were obtained using methods known in theart on a SCINTAG powder X-ray diffractometer model X'TRA equipped with asolid state detector. Copper radiation of 1.5418 Å was used. A roundaluminum sample holder with zero background was used.

DSC analysis was done on a Mettler 821 Star e. The weight of the sampleswas about 5 mg; the samples were scanned at a rate of 10° C./min from30° C. to 200° C. The oven was constantly purged with nitrogen gas at aflow rate of 40 ml/min. Standard 40 μl aluminum crucibles covered bylids with 3 holes were used.

TGA analysis was done using a Mettler M3 meter. The weight of thesamples was about 10 mg; the samples were scanned at a rate of 10°C./min from 25° C. to 200° C. The oven was constantly purged withnitrogen gas at a flow rate of 40 ml/min. Standard 70 μl aluminacrucibles covered by lids with 1 hole were used.

IR analysis was done using a Perkin Elmer “Spectrum One” FT-IRspectrometer in DRIFTt mode. The samples in the 4000-400 cm−1 intervalwere scanned 16 times with 4.0 cm−1 resolution.

The water content of fluvastatin sodium is measured by the methods knownin the art like Karl Fisher or thermogravimetric analysis.

Those skilled in the art will recognize the abbreviations used in thedisclosure, as they are in widespread use in the fields of medicinal andorganic chemistry. The abbreviations used include the following:

-   -   ACN acetonitrile    -   DMF N,N-dimethyl formamide    -   DMSO dimethyl sulfoxide    -   EtOH ethanol    -   Et₂O diethyl ether    -   EtOAc ethyl acetate    -   IPA isopropyl alcohol    -   MeOH methanol    -   MTBE methyl tert-butyl ether    -   MEK methyl ethyl ketone    -   THF tetrahydrofuran

Preparative

All the preparations described below were carried out on fluvastatinsodium Form B except where indicated otherwise. Fluvastatin sodium FormsXIX-1, XXXIII, XXXIV, XXXV were prepared using as starting materialfluvastatin sodium Form XV which was purchased from Zhejiang HisunPharmaceutical Company Limited; 46 Waisha Road, Jiaojiang District,Taizhou City, Zhejiang Province, China.

1) Preparation of Fluvastatin Sodium Crystal Form I Example 1

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) andNaOH (0.29 g) partially dissolved in acetone (0.75 ml) was added. Themixture was stirred at room temperature overnight. The product wasisolated by filtration under nitrogen, washed with acetone (40 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 2.31 g (76.2%) offluvastatin sodium crystal Form I.

Example 2

Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml)by heating and NaOH (0.28 g) was added. The mixture was stirred at about60EC for 1 h, cooled to room temperature, heated again to about 75EC for2 h, then cooled to room temperature and stirred overnight. The productwas isolated by filtration under nitrogen, washed with acetonitrile (40ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.07 g (34.9%)of fluvastatin sodium crystal Form I.

Example 3

Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml)by heating and a solution of NaOH (0.28 g) in water (0.75 ml) was addedat about 50EC. The mixture was stirred at about 40EC for 2 h, cooled toroom temperature and stirred for another h. The product was isolated byfiltration under nitrogen, washed with acetonitrile (40 ml) and dried at50EC in a vacuum oven for 24 h to obtain 2.52 g (82.2%) of fluvastatinsodium crystal Form I.

Example 4

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in acetone (600ml) at reflux temperature. The obtained solution was filtered and MTBE(200 ml) was added at reflux temperature. The solution was cooled toroom temperature and MTBE (100 ml) was added. The mixture wasconcentrated under reduced pressure to obtain precipitate. The productwas then filtered, washed with MTBE (2×18 ml) and dried at 50EC in avacuum oven for 24 h to obtain 1.7 g (58%) of fluvastatin sodium crystalForm I.

Example 5

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-2-ol(60 ml) and water (6 ml) at reflux temperature. The solution was cooledto 15EC for 2 h to obtain a precipitate. The product was then filteredunder nitrogen flow, washed with butan-2-ol (1×15 ml) and dried at 50ECin a vacuum oven for 24 h to obtain 0.05 g (2%) of fluvastatin sodiumcrystal Form I.

2) Preparation of Fluvastatin Sodium Crystal Form II Example 6

Fluvastatin sodium crystal Form B (3.0 g) was almost completelydissolved in butan-1-ol (90 ml) at reflux temperature. The mixture wasstirred at reflux temperature for 2.5 h. Then, it was cooled to roomtemperature and stirred at this temperature for 16 h. The product wasfiltered, washed with butan-1-ol (1×5 ml) and dried at 50EC in a vacuumoven for 52 h to obtain 1.7 g (56%) of fluvastatin sodium crystal FormII.

3) Preparation of Fluvastatin Sodium Crystal Form III Example 7

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. MTBE (70 ml) was added dropwise and themixture was stirred at reflux temperature for 3 h. The solution wascooled to room temperature and MTBE (70 ml) was added to obtain amassive precipitate after 2 h. The product was filtered, washed withMTBE (3×10 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.5g (49%) of fluvastatin sodium crystal Form III.

Example 8

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. The solution was filtered and n-hexane(70 ml) was added dropwise. The mixture was stirred at refluxtemperature for 3.5 h. The solution was cooled to room temperature toobtain precipitate. The product was filtered, washed with n-hexane (2×20ml) and dried at 50EC in a vacuum oven for 23 h to obtain 1.0 g (34%) offluvastatin sodium crystal Form III.

Example 9

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane(75 ml) at reflux temperature. The solution was cooled to roomtemperature to obtain precipitate. The product was filtered, washed with1,4-dioxane (1×25 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 2.2 g (75%) of fluvastatin sodium crystal Form III.

Example 10

A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethylacetate (150 ml) was stirred at reflux temperature. Hexanes (150 ml)were added dropwise at reflux temperature. The mixture was stirred atreflux temperature for 3 h. The suspension was cooled to roomtemperature. The product was filtered under nitrogen flow, washed withhexanes (1×20 ml) and dried at 50EC in a vacuum oven for 22 h to obtain2.7 g (91%) of fluvastatin sodium crystal Form III.

Example 11

Amorphous fluvastatin sodium (1.7 g) was dissolved in ethanol (10 ml) atreflux temperature. After 0.5 h the product was recrystallized at refluxtemperature. The suspension was stirred at reflux temperature foradditional 1 h. Then, the suspension was cooled to room temperature andadditional amount of ethanol (10 ml) was added. The product was filteredunder nitrogen flow, washed with ethanol (2×10 ml) and dried at 50EC ina vacuum oven for 24 h to obtain 0.9 g (53%) of fluvastatin sodiumcrystal Form III.

Example 12

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (50 ml)at reflux temperature. Cyclohexane (65 ml) was added dropwise at refluxtemperature to obtain a precipitate. The mixture was cooled to roomtemperature. The product was filtered, washed with cyclohexane (2×20 ml)and dried at 50EC in a vacuum oven for 19.5 h to obtain 2.7 g (91%) offluvastatin sodium crystal Form III.

Example 13

A suspension of fluvastatin sodium crystal Form XIV (3.0 g) was stirredin ethanol (20 ml) at reflux temperature for 7 h. The suspension wascooled to room temperature. The product was filtered under nitrogenflow, washed with ethanol (2×25 ml) and dried at 50EC in a vacuum ovenfor 21 h to obtain 2.3 g (77%) of fluvastatin sodium crystal Form III.

4) Preparation of Fluvastatin Sodium Crystal Form IV Example 14

Fluvastatin sodium (3.0 g) was dissolved in tetrahydrofuran (THF) (50ml) at reflux temperature. Chloroform (50 ml) was added dropwise atreflux temperature and the resulting mixture was stirred at thistemperature for 40 minutes. A precipitate was obtained during reflux.Then, the mixture was cooled to room temperature. The product wasisolated by filtration under nitrogen, washed with Chloroform (2×20 ml)and dried at 50EC in a vacuum oven for 19 h to obtain 2.7 g (89%) offluvastatin sodium crystal Form IV.

Example 5

Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at refluxtemperature. Dichloromethane (65 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 1 h. Then, the mixture was cooled to room temperature. The productwas isolated by filtration under nitrogen, washed with dichloromethane(2×20 ml) and dried at 50EC in a vacuum oven for 20 h to obtain 2.6 g(87%) of fluvastatin sodium crystal Form IV.

Example 16

Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at refluxtemperature. 1,2-Dichloroethane (50 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 1 h. A precipitate was obtained during the reflux. Then, the mixturewas cooled to room temperature. The product was isolated by filtrationunder nitrogen and dried at 50EC in a vacuum oven for 24 h to obtain 0.7g (24%) of fluvastatin sodium crystal Form IV.

Example 17

Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at refluxtemperature. Diethyl ether (50 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 1 h. A precipitate was obtained during the reflux. Then, the mixturewas cooled to room temperature. The product was isolated by filtrationunder nitrogen, washed with diethyl ether (2×25 ml) and dried at 50EC ina vacuum oven for 24.5 h to obtain 2.1 g (69%) of fluvastatin sodiumcrystal Form IV.

Example 18

Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at refluxtemperature. n-Pentane (50 ml) was added dropwise at reflux temperatureand the resulting mixture was stirred at this temperature for 8 minutes.A massive precipitate was obtained during reflux. Then, the mixture wascooled to room temperature. The product was isolated by filtration undernitrogen, washed with n-pentane (2×25 ml) and dried at 50EC in a vacuumoven for 25 h to obtain 2.8 g (93%) of fluvastatin sodium crystal FormIV.

Example 19

Fluvastatin sodium (3.0 g) was dissolved in butan-1-ol (70 ml) at refluxtemperature. Cyclohexane (70 ml) was added at reflux temperature and theresulting mixture was stirred at this temperature for 3 h. Then, themixture was cooled to room temperature. The product was isolated byfiltration, washed with cyclohexane (2×20 ml) and dried at 50EC in avacuum oven for 25.5 h to obtain 2.1 g (69%) of fluvastatin sodiumcrystal Form IV.

Example 20

Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (75 ml) atreflux temperature. Cyclohexane (70 ml) was added at reflux temperatureand the resulting mixture was stirred at this temperature for 3.5 h. Aprecipitate was obtained during the reflux. Then, the mixture was cooledto room temperature. The product was isolated by filtration, washed withcyclohexane (2×10 ml) and dried at 50EC in a vacuum oven for 22.5 h toobtain 2.7 g (89%) of fluvastatin sodium crystal Form IV.

Example 21

Fluvastatin sodium (3.0 g) was dissolved in propan-2-ol (70 ml) atreflux temperature. MTBE (70 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 15 minutes. A precipitate was obtained during the reflux. Then, themixture was cooled to room temperature. The product was isolated byfiltration under nitrogen, washed with MTBE (3×20 ml) and dried at 50ECin a vacuum oven for 25.5 h to obtain 2.4 g (81%) of fluvastatin sodiumcrystal Form IV.

5) Preparation of Fluvastatin Sodium Crystal Form IV-1 Example 22

Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at refluxtemperature. n-Heptane (50 ml) was added dropwise at reflux temperatureand the resulting mixture was stirred at this temperature for 1 h. Amassive precipitate was obtained during reflux. Then, the mixture wascooled to room temperature. The product was isolated by filtration undernitrogen, washed with n-heptane (2×50 ml) and dried at 50EC in a vacuumoven for 24 h to obtain 2.9 g (97%) of fluvastatin sodium crystal FormIV-1.

Example 23

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. Cyclohexane (70 ml) was added at reflux temperature andthe resulting mixture was stirred at this temperature for 5 h. Then, themixture was cooled to room temperature. The product was isolated byfiltration, washed with cyclohexane (1×20 ml) and dried at 50EC in avacuum oven for 24 h to obtain 3.0 g (100%) of fluvastatin sodiumcrystal Form IV-1.

Example 24

Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (75 ml) atreflux temperature. MTBE (75 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 4 h. A massive precipitate was obtained during the reflux. Then, themixture was cooled to room temperature. The product was isolated byfiltration, washed with MTBE (2×10 ml) and dried at 50EC in a vacuumoven for 22 h to obtain 2.7 g (89%) of fluvastatin sodium crystal FormIV-1.

6) Preparation of Fluvastatin Sodium Crystal Form V Example 25

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. The solution was filtered and n-heptane(70 ml) was added dropwise at reflux temperature. The mixture wasstirred at reflux temperature for additional 3 h. The mixture was cooledto room temperature and stirred at this temperature for 25 h. Theproduct was filtered, washed with n-Heptane (1×20 ml) and dried at 50ECin a vacuum oven for 24 h to obtain 1.8 g (61%) of fluvastatin sodiumcrystal Form V.

Example 26

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in a mixture ofethanol (50 ml), ethyl acetate (20 ml) and propan-1-ol (10 ml) at refluxtemperature. The solution was filtered and n-hexane (200 ml) was addeddropwise. The mixture was cooled to room temperature and stirred at thistemperature for 16 h. The product was filtered under nitrogen flow,washed with n-hexane (2×25 ml) and dried at 50EC in a vacuum oven for 24h to obtain 2.3 g (77%) of fluvastatin sodium crystal Form V.

7) Preparation of Fluvastatin Sodium Crystal Form VI Example 27

Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at roomtemperature. Diethyl ether (100 ml) was added gradually at roomtemperature and the resulting mixture was stirred at this temperaturefor 1 h. Then, the mixture was cooled using an ice-bath. The product wasisolated by filtration under nitrogen and dried at 50EC in a vacuum ovenfor 24 h to obtain 1.7 g (55%) of fluvastatin sodium crystal Form VI.

Example 28

Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at roomtemperature. Then, hexanes (10 ml) were added. The solvent and theanti-solvent were evaporated to dryness and the obtained solid wassuspended in DMF (80 ml) at room temperature for 16 h. The mixture wascooled using an ice-bath. The product was isolated by filtration undernitrogen and dried at 50EC in a vacuum oven for 24 h to obtain 1.3 g(42%) of a mixture of fluvastatin sodium crystal Forms VI and VII.

Example 29

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred atabout 60EC for 4 hr, after which the starting material was no longerdetectable by HPLC. Then, acetonitrile (58 ml) was dripped into thesolution over 1.5 h. Turbidity appeared in the solution which as it wasallowed to cool slowly to room temperature. The mixture was stirredovernight. The product was isolated by filtration under nitrogen, washedwith acetonitrile (50 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 2.23 g (73%) of fluvastatin sodium Form VI.

Example 30

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in methanol (5 ml). The mixture was heated to reflux and stirred for2.25 h after which the starting material was not longer detected byHPLC. Then, acetonitrile (40 ml) was dripped into the solution in twoportions over 1.5 h. The mixture was cooled slowly to room temperatureand stirred for another 1.75 h. The product was isolated by filtrationunder nitrogen, washed with acetonitrile (20 ml) and dried at 50EC in avacuum oven for 23 h to obtain 1.7 g (83.4%) of fluvastatin sodium FormVI.

Example 31

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in ethanol (15 ml). The mixture was stirred at about 70EC for 1.75 h,after which the starting material was not detected by HPLC. Then,acetone (40 ml) was dripped into the solution and the mixture was cooledslowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetone (20 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 1.54 g (75.6%) offluvastatin sodium Form VI.

Example 32

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in water (0.5 ml) and butan-1-ol (8 ml). The mixture was stirred atabout 8EC for 4 h, after which the starting material was not detected byHPLC. Then, acetonitrile (40 ml) was dripped into the solution and themixture was cooled slowly to room temperature and stirred overnight. Theproduct was isolated by filtration under nitrogen, washed withacetonitrile (15 ml) and dried at 50EC in a vacuum oven for 24 h toobtain fluvastatin sodium Form VI (1.65 g, 81%).

8) Preparation of Fluvastatin Sodium Crystal Form VII Example 33

Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at roomtemperature. Chloroform (100 ml) was added gradually at room temperatureand the resulting mixture was stirred at this temperature for 4 days.Then, the mixture was cooled using an ice-bath. The product was isolatedby filtration under nitrogen, washed with dichloromethane (1×35 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 2.0 g (65%) offluvastatin sodium crystal Form VII.

Example 34

Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at roomtemperature. MTBE (100 ml) was added gradually at room temperature andthe resulting mixture was stirred at this temperature for 5 h. Then, themixture was cooled using an ice-bath. The product was isolated byfiltration under nitrogen and dried at 50EC in a vacuum oven for 22 h toobtain 1.8 g (59%) of fluvastatin sodium crystal Form VII.

Example 35

Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at roomtemperature. Dichloromethane (100 ml) was added gradually at roomtemperature and the resulting mixture was stirred at this temperaturefor 16 h. Then, the mixture was cooled using an ice-bath. The productwas isolated by filtration under nitrogen and dried at 50EC in a vacuumoven for 23 h to obtain 2.4 g (79%) of fluvastatin sodium crystal FormVII.

Example 36

Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at roomtemperature. Then, cyclohexane (20 ml) was added. The solvent and theanti-solvent were evaporated to dryness and the obtained solid wassuspended in DMF (80 ml) at room temperature for 16 h. The mixture wascooled using an ice-bath. The product was isolated by filtration undernitrogen and dried at 50EC in a vacuum oven for 23 h to obtain 1.9 g(64%) of fluvastatin sodium crystal Form VII.

Example 37

Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at roomtemperature. 1,2-Dichloroethane (100 ml) was added at room temperatureand the resulting mixture was stirred at this temperature for 5 h. Then,the mixture was cooled using an ice-bath. The product was isolated byfiltration under nitrogen and dried at 50EC in a vacuum oven for 21 h toobtain 1.8 g (60%) of fluvastatin sodium crystal Form VII.

Example 38

Fluvastatin sodium (3.0 g) was suspended in DMF (40 ml) at roomtemperature for 16 h. The product was isolated by filtration undernitrogen, washed with DMF (1×20 ml) and dried at 50EC in a vacuum ovenfor 28 h to obtain 1.1 g (37%) of fluvastatin sodium crystal Form VII.

Example 39

Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.)and butan-1-ol (15 ml). The mixture was stirred at about 80EC for 1.5 h,after which the starting material was not detected by HPLC. Then, 40 mlof acetone was dripped into the solution and the mixture was cooledslowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetone (20 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 1.09 g (53.5%) offluvastatin sodium Form VII.

Example 40

Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.)and butan-1-ol (15 ml). The mixture was stirred at about 80EC for 2.5 h,after which the starting material was not detected by HPLC. Then, 40 mlof acetonitrile was dripped into the solution. The mixture was thencooled slowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetonitrile (45 ml)and dried at 50EC in a vacuum oven for 24 h to obtain 1.96 g (96.2%) offluvastatin sodium Form VII.

Example 41

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated toreflux and 1 ml of propan-2-ol was added. After 2 h the mixture wascooled to room temperature and stirred for 2 h. MTBE (60 ml) was drippedinto the solution over 20 min and it was stirred for another 1.5 h. Theproduct was isolated by filtration under nitrogen, washed with MTBE anddried at 50EC in a vacuum oven for 24 h to obtain 1.9 g (62%) offluvastatin sodium Form VII.

Example 42

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in MeOH (30 ml). The mixture was stirred at room temperature for 4.5 h.Then, it was filtered and concentration by vacuum distillation until asolid appeared. The concentrated solution was heated to reflux and 60 mlof acetonitrile was dripped into the mixture over 50 min. Turbidity wasobserved and the mixture was cooled slowly to room temperature andstirred over night. The product was isolated by filtration undernitrogen, washed with acetonitrile (60 ml) and dried at 50EC in a vacuumoven for 24 h to obtain fluvastatin sodium Form VII (2.54 g, 83.1%).

Example 43

Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) andthe mixture was heating to about 40EC for dissolution. A solution ofNaOH (1 eq.) in EtOH (7.5 ml) was added and turbidity was immediatelyobserved. The mixture then was heated to about 65EC. The mixture wascooled slowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetonitrile (40 ml)and dried at 50EC in a vacuum oven for 24 h to obtain fluvastatin sodiumForm VII (1.99 g, 64.9%).

9) Preparation of Fluvastatin Sodium Crystal Form IX Example 44

Into a 100 ml flask were placed fluvastatin methyl ester (3.0 g), EtOH(7.5 ml) and a solution of NaOH (0.28 g) in water (0.75 ml). The mixturewas heated to reflux for two h, propan-2-ol was added (58 ml) and themixture was cooled to room temperature and stirred over night. Theproduct was isolated by filtration under nitrogen, washed withpropan-2-ol (50 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 1.92 g (62.8%) of fluvastatin sodium crystal Form IX.

Example 45

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane(75 ml) at reflux temperature. Dichloromethane (75 ml) was addeddropwise to obtain a precipitate and the mixture was stirred at refluxtemperature for 2.5 h. The suspension was cooled to room temperature andstirred at this temperature for 20 h. The product was filtered, washedwith Dichloromethane (1×20 ml) and dried at 50EC in a vacuum oven for 24h to obtain 1.5 g (51%) of fluvastatin sodium crystal Form IX.

Example 46

A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethylacetate (100 ml) was stirred at reflux temperature for 2.5 h. Thesuspension was cooled to room temperature. The product was filtered,washed with ethyl acetate (1×20 ml) and dried at 50EC in a vacuum ovenfor 23 h to obtain 2.0 g (66%) of fluvastatin sodium crystal Form IX.

Example 47

Fluvastatin sodium crystal Form B (5.0 g) was almost completelydissolved in ethanol (100 ml) at 45EC. The solution was filtered andcooled to room temperature. ethyl acetate (250 ml) was added and themixture was stirred at room temperature for 63 h to obtain precipitate.The product was filtered under nitrogen flow, washed with ethyl acetate(1×20 ml) and dried at 50EC in a vacuum oven for 23 h to obtain 2.2 g(44%) of fluvastatin sodium crystal Form IX.

Example 48

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130ml) at room temperature. The solution was filtered and Diethyl ether(260 ml) was added. The mixture was stirred at room temperature for 16 hto obtain precipitate. The product was filtered and dried at 50EC in avacuum oven for 22 h to obtain 1.7 g (56%) of fluvastatin sodium crystalForm IX.

Example 49

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130ml) at room temperature. The solution was filtered and n-pentane (260ml) was added. The mixture was stirred at room temperature for 17 h toobtain precipitate. The product was filtered, washed with n-pentane(2×35 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.9 g(63%) of fluvastatin sodium crystal Form IX.

Example 50

Fluvastatin sodium crystal Form B (5.0 g) was almost completelydissolved in a mixture of ethanol (130 ml) and methanol (5 ml) at roomtemperature. The solution was filtered and hexanes (200 ml) were addeddropwise. The mixture was stirred at room temperature for 19 h to obtainprecipitate. The product was filtered under nitrogen flow and dried at50EC in a vacuum oven for 22 h to obtain 3.6 g (73%) of fluvastatinsodium crystal Form IX.

10) Preparation of Fluvastatin Sodium Crystal Form IX-1 Example 51

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. The solution was filtered and n-pentane(70 ml) was added dropwise at reflux temperature. The mixture wasstirred at reflux temperature for 1.5 h. The mixture was cooled to roomtemperature. The product was filtered, washed with n-pentane (2×10 ml)and dried at 50EC in a vacuum oven for 21 h to obtain 2.2 g (73%) offluvastatin sodium crystal Form IX-1.

Example 52

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. The solution was filtered and Diethylether (70 ml) was added dropwise at reflux temperature. The mixture wasstirred at reflux temperature for 0.5 h. The mixture was cooled to roomtemperature. The product was filtered, washed with Diethyl ether (2×5ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.0 g (65%) offluvastatin sodium crystal Form IX-1.

Example 53

A slurry of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate(240 ml) was heated to reflux temperature. Additional amount of ethylacetate (80 ml) was added at reflux temperature. The material wasrecrystallized during reflux and the mixture was stirred at refluxtemperature for 2.5 h to obtain a massive precipitate. The mixture wascooled to room temperature. The product was filtered under nitrogenflow, washed with ethyl acetate (2×10 ml) and dried at 50EC in a vacuumoven for 23 h to obtain 2.7 g (89%) of fluvastatin sodium crystal FormIX-1.

Example 54

A slurry of fluvastatin sodium crystal Form B (3.0 g) in isobutylacetate (70 ml) was heated to reflux temperature. The material wasrecrystallized during reflux and MTBE (70 ml) was added dropwise toobtain a massive precipitate. The mixture was stirred at refluxtemperature for additional 0.5 h. The mixture was cooled to roomtemperature. The product was filtered under nitrogen flow, washed withMTBE (2×10 ml) and dried at 50EC in a vacuum oven for 22 h to obtain2.74 g (91%) of fluvastatin sodium crystal Form IX-1.

Example 55

Fluvastatin sodium crystal Form B (3.0 g) was almost completelydissolved in isobutyl acetate (70 ml) at reflux temperature.Dichloromethane (70 ml) was added dropwise to obtain precipitate. Themixture was cooled to room temperature. The product was filtered, washedwith Dichloromethane (2×10 ml) and dried at 50EC in a vacuum oven for 25h to obtain 2.5 g (82%) of fluvastatin sodium crystal Form IX-1.

Example 56

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130ml) at room temperature. The solution was filtered and hexanes (200 ml)were added dropwise. The mixture was stirred at room temperature for 19h. The product was filtered under nitrogen flow, washed with hexanes(2×25 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.2 g(41%) of amorphous fluvastatin sodium. A precipitate was observed in themother-liquid after 20 days. The precipitate was dried at 50EC in avacuum oven for 26 h to obtain fluvastatin sodium crystal Form IX-1.

Example 57

A slurry of fluvastatin sodium crystal Form B (3.0 g) in toluene (60 ml)and Cyclohexane (60 ml) was heated to reflux temperature for 22 h. Themixture was cooled to room temperature. The product was filtered undernitrogen flow and dried at 50EC in a vacuum oven for 24 h to obtain 2.6g (85%) of fluvastatin sodium crystal Form IX-1.

Example 58

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (100 ml)at reflux temperature. The solution was filtered and hexanes (100 ml)were added dropwise at reflux temperature. The mixture was stirred atreflux temperature for 1 h and then was cooled to room temperature. Theproduct was filtered under nitrogen flow, washed with hexanes (2×20 ml)and dried at 50EC in a vacuum oven for 19 h to obtain 2.5 g (83%) offluvastatin sodium crystal Form IX-1.

Example 59

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (60 ml)at reflux temperature. The solution was filtered and MTBE (60 ml) wasadded dropwise at reflux temperature. The mixture was stirred at refluxtemperature for 1 h and then was cooled to room temperature. The productwas filtered under nitrogen flow, washed with MTBE (2×20 ml) and driedat 50EC in a vacuum oven for 18 h to obtain 1.9 g (63%) of fluvastatinsodium crystal Form IX-1.

Example 60

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in MEK (70 ml)at reflux temperature. MTBE (70 ml) was added dropwise at refluxtemperature. The mixture was cooled to room temperature. The product wasfiltered under nitrogen flow and dried at 50EC in a vacuum oven for 29 hto obtain 0.7 g (24%) of fluvastatin sodium crystal Form IX-1.

11) Preparation of Fluvastatin Sodium Crystal Form XI Example 61

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. Hexanes (70 ml) were added at reflux temperature toobtain a massive precipitate. The resulting suspension was stirred atreflux temperature for 4.5 h. Then, the mixture was cooled to roomtemperature. The product was isolated by filtration, washed with hexanes(2×15 ml) and dried at 50EC in a vacuum oven for 23.5 h to obtain 2.8 g(93%) of fluvastatin sodium crystal Form XI.

Example 62

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. n-pentane (70 ml) was added at reflux temperature toobtain a massive precipitate. The resulting suspension was stirred atreflux temperature for 4 h. Then, the mixture was cooled to roomtemperature. The product was isolated by filtration, washed withn-pentane (2×10 ml) and dried at 50EC in a vacuum oven for 23.5 h toobtain 2.76 g (92%) of fluvastatin sodium crystal Form XI.

Example 63

Fluvastatin sodium (3.0 g) was dissolved in butan-2-ol (70 ml) at refluxtemperature. MTBE (70 ml) was added at reflux temperature to obtain amassive precipitate. The resulting suspension was stirred at refluxtemperature for 5 h. Then, the mixture was cooled to room temperature.The product was isolated by filtration, washed with MTBE (2×10 ml) anddried at 50EC in a vacuum oven for 21 h to obtain 2.7 g (90%) offluvastatin sodium crystal Form XI.

Example 64

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. Diethyl ether (70 ml) was added at reflux temperature toobtain a massive precipitate. The resulting suspension was stirred atreflux temperature for 4.5 h. Then, the mixture was cooled to roomtemperature. The product was isolated by filtration, washed with diethylether (2×10 ml) and dried at 50EC in a vacuum oven for 24 h to obtain2.8 g (94%) of fluvastatin sodium crystal Form XI.

Example 65

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. n-heptane (70 ml) was added at reflux temperature toobtain a massive precipitate. The resulting suspension was stirred atreflux temperature for 4.5 h. Then, the mixture was cooled to roomtemperature. The product was isolated by filtration, washed withn-heptane (2×10 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 2.8 g (94%) of fluvastatin sodium crystal Form XI.

Example 66

Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol(70 ml) at reflux temperature. During this time the material wasrecrystallized. Chloroform (70 ml) was added dropwise at refluxtemperature to obtain a massive precipitate. The resulting suspensionwas stirred at reflux temperature for 4 h. Then, the mixture was cooledto room temperature. The product was isolated by filtration, washed withChloroform (2×10 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 1.7 g (57%) of fluvastatin sodium crystal Form XI.

12) Preparation of Fluvastatin Sodium Crystal Form XI-2 Example 67

Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) atreflux temperature. Hexanes (60 ml) were added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 1.5 h. Then, the mixture was cooled to room temperature. The productwas isolated by filtration under nitrogen, washed with hexanes (2×20 ml)and dried at 50EC in a vacuum oven for 28 h to obtain 2.3 g (78%) offluvastatin sodium crystal Form XI-2.

Example 68

Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) atreflux temperature. MTBE (60 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 40 minutes. Then, the mixture was cooled to room temperature. Theproduct was isolated by filtration under nitrogen, washed with MTBE(2×30 ml) and dried at 50EC in a vacuum oven for 28 h to obtain 2.5 g(82%) of fluvastatin sodium crystal Form XI-2.

Example 69

Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) atreflux temperature. Dichloromethane (60 ml) was added dropwise at refluxtemperature and the resulting mixture was stirred at this temperaturefor 30 minutes. Then, the mixture was cooled to room temperature. Theproduct was isolated by filtration under nitrogen, washed withdichloromethane (2×20 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 0.3 g (11%) of fluvastatin sodium crystal Form XI-2.

13) Preparation of Fluvastatin Sodium Crystal Form XII Example 70

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol(70 ml) at reflux temperature. 1,4-dioxane (140 ml) was added in twoportions (2×70 ml) at reflux temperature during 18 h. Then, the turbidsolution was cooled to room temperature and another portion of1,4-dioxane (70 ml) was added. The mixture was stirred at roomtemperature for 23 h. Then, it was concentrated under reduced pressureand was stirred at room temperature for 9.5 h to obtain a precipitate.The product was filtered under nitrogen flow, washed with 1,4-dioxane(2'15 ml) and dried at 50EC in a vacuum oven for 20 h to obtain 0.35 g(12%) of fluvastatin sodium crystal Form XII.

14) Preparation of Fluvastatin Sodium Crystal Form XIII Example 71

A suspension of fluvastatin sodium crystal Form B (3.0 g) inacetonitrile (600 ml) was stirred at reflux temperature for 2 h. Thesuspension was then cooled to 10EC using an ice-bath. The product wasfiltered under nitrogen flow and dried at 50EC in a vacuum oven for 24 hto obtain 2.1 g (70%) of fluvastatin sodium crystal Form XIII.

15) Preparation of Fluvastatin Sodium Crystal form XVI

Example 72

Fluvastatin sodium (3.0 g) was almost completely dissolved inpropan-2-ol (70 ml) at reflux temperature. Dichloromethane (70 ml) wasadded dropwise at reflux temperature. The resulting solution was stirredat reflux temperature for 3 h. Then, the mixture was cooled to roomtemperature and stirred at this temperature for 16 h. The product wasisolated by filtration, washed with dichloromethane (2×10 ml) and driedat 50EC in a vacuum oven for 22 h to obtain 1.3 g (44%) of fluvastatinsodium crystal Form XVI.

16) Preparation of Fluvastatin Sodium Crystal Form XVII Example 73

Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) atreflux temperature. The resulting solution was stirred at refluxtemperature for 3 h. During this time the material was recrystallized.Then, the mixture was cooled to room temperature. The product wasisolated by filtration under nitrogen, washed with propan-1-ol (1×10 ml)and dried at 50EC in a vacuum oven for 21 h to obtain 0.2 g (7%) offluvastatin sodium crystal Form XVII.

17) Preparation of Fluvastatin Sodium Crystal Form XVIII Example 74

Fluvastatin sodium (3.0 g) was suspended in MEK (30 ml) at refluxtemperature for 16 h. Then, the solvent was distilled out and theresidue was dried in a vacuum oven for 24 h to obtain 2.7 g (90%) offluvastatin sodium crystal Form XVIII.

Example 75

Fluvastatin sodium (3.0 g) was suspended in MEK (30 ml) at refluxtemperature for 2.5 h. Then, the mixture was cooled to room temperature.The product was isolated by filtration under nitrogen, washed with MEK(2×15 ml) and dried at 50EC in a vacuum oven for 25.5 h to obtain 2.6 g(86%) of fluvastatin sodium crystal Form XVIII.

18) Preparation of Fluvastatin Sodium Crystal Form XIX Example 76

Fluvastatin sodium Form XI (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 80% for 11 days. Fluvastatin sodium Form XIX wasrecovered.

Example 77

Fluvastatin sodium Form XI (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 100% for 11 days. Fluvastatin sodium Form XIX wasrecovered.

Example 78

Fluvastatin sodium Form IV-I (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 80% for 11 days . Fluvastatin sodium Form XIX wasrecovered.

Example 79

Fluvastatin sodium Form IV-1 (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 100% for 11 days . Fluvastatin sodium Form XIX wasrecovered.

Example 80

Fluvastatin sodium Form XVI (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 80% for 24 days. Fluvastatin sodium Form XIX wasrecovered.

Example 81

Fluvastatin sodium Form XVI (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 100% for 24 days. Fluvastatin sodium Form XIX wasrecovered.

19) Preparation of Fluvastatin Sodium Crystal Form XIX-1 Example 82

Wet fluvastatin sodium crystal form XI (10.0 g) was stirred in water (10ml) at room temperature for 6 h. Then, the product was filtered undernitrogen flow, washed with water (2 ml) and dried at 50EC in a vacuumoven for 21.5 h to obtain 3.8 g of fluvastatin sodium crystal formXIX-1.

20) Preparation of Fluvastatin Sodium Crystal Form XX Example 83

Fluvastatin sodium Form XVI (˜300 mg) was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 80% for 1 days. Fluvastatin sodium Form XX wasrecovered.

21) Preparation of Fluvastatin Sodium Crystal Form XXII Example 84

About 300 mg fluvastatin sodium Form XV was placed on flat dishes with adiameter of 35 mm and introduced in a chamber with controlled relativehumidity of about 100% for 14 days, and fluvastatin sodium Form XXII wasrecovered.

22) Preparation of Fluvastatin Sodium Crystal Form XXIII Example 85

Fluvastatin sodium crystal Form B (5.0 g) was dissolved in propan-1-ol(100 ml) at reflux temperature. The material was recrystallized atreflux temperature after 1 h. The suspension was stirred at refluxtemperature for additional 2 h. Then, the mixture was cooled to roomtemperature and stirred at this temperature for 16 h to obtain a massiveprecipitation. The product was filtered under nitrogen flow, washed withpropan-1-ol (2×25 ml) and dried at 50EC in a vacuum oven for 72 h toobtain 3.3 g (66%) of fluvastatin sodium crystal Form XXIII.

23) Preparation of Fluvastatin Sodium Crystal Form XXIV Example 86

Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (14ml) at reflux temperature. The mixture was stirred at reflux temperaturefor 1.5 h and then was cooled to room temperature. The mixture wasstirred at room temperature for 16 h to obtain a massive precipitate.The product was filtered under nitrogen flow, washed with water (2×3 ml)and dried at 50EC in a vacuum oven for 22 h to obtain 4.5 g (90%) offluvastatin sodium crystal Form XXIV.

Example 87

Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (9 ml)at reflux temperature. The mixture was stirred at reflux temperature for1.5 h and then was cooled to room temperature. The mixture was stirredat room temperature for 16 h to obtain a massive precipitate. Theproduct was filtered under nitrogen flow, washed with water (1×5 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 4.2 g (84%) offluvastatin sodium crystal Form XXIV.

Example 88

Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (5 ml)at reflux temperature. The mixture was stirred at reflux temperature for2 h and then was cooled to room temperature. The product was dried(without filtration) at 50EC in a vacuum oven for 24 h to obtain 4.4 g(88%) of fluvastatin sodium crystal Form XXIV.

Example 89

A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml)was stirred at room temperature for 1 h. Diethyl ether (100 ml) wasadded and the mixture was stirred for 5 minutes. The organic and aqueousphases were separated. Traces of diethyl ether were removed from theaqueous phase under reduced pressure. The aqueous solution waslyophilized for 72 h to obtain fluvastatin sodium crystal Form XXIV.

Example 90

A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml)was stirred at room temperature for 1 h. Diethyl ether (100 ml) wasadded and the mixture was stirred for 15 minutes. The organic andaqueous phases were separated. Traces of Diethyl ether were removed fromthe aqueous phase under reduced pressure. The aqueous solution waslyophilized for 96 h to obtain fluvastatin sodium crystal Form XXIV.

24) Preparation of Fluvastatin Sodium Crystal Form XXVI Example 91

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane(20 ml) and water (1 ml) at reflux temperature. The solution was stirredat reflux temperature for 1 h. Then, the mixture was cooled to roomtemperature and stirred at this temperature for 1.5 h to obtain amassive precipitation. The product was dried at 50EC in a vacuum oven(without isolation by filtration) for 22 h to obtain 3.2 g (107%) offluvastatin sodium crystal Form XXVI.

25) Preparation of Fluvastatin Sodium Crystal Form XXVII Example 92

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane(20 ml) and water (1 ml) at reflux temperature. Hexanes (30 ml) wereadded dropwise at reflux temperature and the obtained mixture wasstirred at this temperature for additional 1 h. Then, the mixture wascooled to room temperature and stirred at this temperature for 1 h toobtain a massive precipitation. The product was isolated by filtration,washed with hexanes (3×20 ml) and dried at 50EC in a vacuum oven for 22h to obtain 2.5 g (82%) of fluvastatin sodium crystal Form XXVII.

26) Preparation of Fluvastatin Sodium Crystal Form XXIX Example 93

Fluvastatin sodium crystal Form XV (5.0 g) was stirred in 1,4-dioxane(80 ml) at reflux temperature for 16 h. Then, the suspension was cooledto room temperature. The product was filtered under nitrogen flow,washed with 1,4-dioxane (4×25 ml) and dried at 50EC in a vacuum oven for24 h to obtain 3.8 g (76%) of fluvastatin sodium crystal Form XXIX.

27) Preparation of Fluvastatin Sodium Crystal Form XXX Example 94

fluvastatin sodium crystal Form XV (5.0 g) was stirred inmethylethylketone (MEK) (70 ml) at reflux temperature for 16 h. Then,the suspension was cooled to room temperature. The product was filteredunder nitrogen flow, washed with MEK (4×15 ml) and dried at 50EC in avacuum oven for 22 h to obtain 4.2 g (84%) of fluvastatin sodium crystalForm XXX.

Example 95

Fluvastatin sodium crystal Form XV (5.0 g) was stirred intetrahydrofuran (THF) (50 ml) at reflux temperature for 16 h. Then, thesuspension was cooled to room temperature. The product was filteredunder nitrogen flow, washed with THF (2×15 ml) and dried at 50EC in avacuum oven for 21 h to obtain 3.9 g (78%) of fluvastatin sodium crystalForm XXX.

Example 96

Fluvastatin sodium crystal Form XV (5.0 g) was stirred in acetone (75ml) at reflux temperature for 16 h. Then, the suspension was cooled toroom temperature. The product was filtered under nitrogen flow, washedwith acetone (3×25 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 4.0 g (80%) of fluvastatin sodium crystal Form XXX.

Example 97

Fluvastatin sodium crystal Form XV (5.0 g) was stirred butan-2-ol (60ml) at reflux temperature for 16 h. Then, the suspension was cooled toroom temperature. The product was filtered under nitrogen flow, washedwith butan-2-ol (3×25 ml) and dried at 50EC in a vacuum oven for 25 h toobtain 4.2 g (84%) of fluvastatin sodium crystal Form XXX.

Example 98

Fluvastatin sodium crystal Form XV (5.0 g) was stirred butan-1-ol (60ml) at reflux temperature for 16 h. Then, the suspension was cooled toroom temperature. The product was filtered under nitrogen flow, washedwith butan-2-ol (4×25 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 4.2 g (84%) of fluvastatin sodium Form XXX.

Example 99

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred atabout 65EC for 3.5 h. Then, another portion of NaOH (0.5 eq.) in water(0.4 ml) was added. After another 40 min the starting material was nolonger detectable by HPLC. Acetone (58 ml) was dripped into the solutionover 25 min. Turbidity appeared in the solution. The mixture was cooledslowly to room temperature and stirred overnight. The product wasisolated by filtration under nitrogen, washed with acetone (20 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 0.25 g (8.2%) offluvastatin sodium Form XXX.

28) Preparation of Fluvastatin Sodium Crystal Form XXXI Example 100

Fluvastatin sodium crystal Form XV (5.0 g) was stirred ethanol (100 ml)at reflux temperature for 23 h. Then, the suspension was cooled to roomtemperature. The product was filtered under nitrogen flow, washed withethanol (2×10 ml) and dried at 50EC in a vacuum oven for 21 h to obtain4.4 g (88%) of fluvastatin sodium crystal Form XXXI.

29) Preparation of Fluvastatin Sodium Crystal Form XXXIII Example 101

Fluvastatin sodium crystal Form XV (5.0 g) was stirred in absoluteethanol (40 ml) at reflux temperature for 16 h. Then, the suspension wascooled to room temperature. The product was filtered under nitrogenflow, washed with absolute ethanol (4×20 ml) and dried at 50EC in avacuum oven for 24 h to obtain 4.2 g (84%) of fluvastatin sodium crystalForm XXXIII.

Example 102

Absolute ethanol was added in 4 portions (1×60 ml, 3×20 ml) tofluvastatin sodium Form B (5.0 g). The heterogeneous mixture was atreflux temperature for 1.25 h. Then, the suspension was cooled to roomtemperature and stirred at this temperature for 23 h. The product wasfiltered under nitrogen flow, washed with absolute ethanol (2×20 ml) anddried at 50EC in a vacuum oven for 22 h to obtain 2.3 g (45%) offluvastatin sodium Form XXXIII.

Example 103

Absolute ethanol was added in two portions (2×100 ml) to fluvastatinsodium Form B (5.0 g). The heterogeneous mixture was at refluxtemperature for 3 h. Then, the suspension was cooled to room temperatureand stirred at this temperature for 18 h. The product was filtered undernitrogen flow, washed with absolute ethanol (1×20 ml) and dried at 50ECin a vacuum oven for 24 h to obtain 0.8 g (16%) of Fluvastatin sodiumForm XXXIII.

30) Preparation of Fluvastatin Sodium Crystal Form XXXIV Example 104

Fluvastatin sodium crystal Form XV (5.0 g) was stirred in DMSO (50 ml)at 100EC for 16 h. Then, the suspension was cooled to room temperature.The product was filtered under nitrogen flow, washed with DMSO (2×25 ml)and dried at 50EC in a vacuum oven for 24 h to obtain 3.6 g (71%) offluvastatin sodium crystal Form XXXIV.

31) Preparation of Fluvastatin Sodium Crystal Form XXXV Example 105

Fluvastatin sodium crystal Form XV (5.0 g) was stirred in DMF (50 ml) at95EC for 16 h. Then, the suspension was cooled to room temperature. Theproduct was filtered under nitrogen flow, washed with DMF (2×25 ml) anddried at 50EC in a vacuum oven for 24 h to obtain 4.9 g (98%) offluvastatin sodium crystal form XXXV.

32) Preparation of Fluvastatin Sodium Crystal Form XXXVI Example 106

A suspension of fluvastatin sodium crystal Form XI wet (10.0 g) in water(10 ml) was stirred at room temperature for 6 h. The product was thenfiltered under nitrogen flow and washed with water (1×2 ml) to obtain9.6 g (88%) of wet fluvastatin sodium crystal Form XXXVI.

33) Preparation of Fluvastatin Sodium Crystal Form XXXVII Example 107

Fluvastatin sodium Form XI (6.0 g) was suspended in water (12 ml) atroom temperature for 5.75 h. Then, the product was filtered undernitrogen flow and dried at 50EC in a vacuum oven for 23 h to obtain 4.1g (68%) of fluvastatin sodium crystal Form XXXVII.

34) Preparation of Fluvastatin Sodium Crystal Form XXXVIII Example 108

Fluvastatin sodium Form XI (2.5 g) was suspended in absolute ethanol(13.5 ml) at reflux temperature for 16 h. Then, the suspension wascooled to room temperature and stirred at this temperature for 3 h. Theproduct was filtered under nitrogen flow, washed with absolute ethanol(2×10 ml) and dried at 50EC in a vacuum oven for 23 h to obtain 2.0 g(79%) of fluvastatin sodium crystal Form XXXVIII.

Example 109

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in EtOH (15 ml). The mixture was stirred at about 70EC for 4 h (itbecame clear and turned to a slurry), after which the starting materialwas not detected by HPLC. Then, 40 ml of ethyl acetate was dripped intothe mixture and it was cooled slowly to room temperature and stirredovernight. The product was isolated by filtration under nitrogen, washedwith ethyl acetate (10 ml) and dried at 50EC in a vacuum oven for 24 hto obtain fluvastatin sodium Form XXXVIII (1.78 g, 87.4%).

Example 110

Fluvastatin sodium crystal Form XI (2.5 g) was suspended in absoluteethanol (13.5 ml) at reflux temperature for 16 h. The suspension wascooled to room temperature and stirred at this temperature for 3 h. Theproduct was filtered under nitrogen flow, washed with absolute ethanol(2×10 ml) and dried at 50EC in a vacuum oven for 23 h to obtain 2.0 g(79%) of fluvastatin sodium crystal Form XXXVIII.

35) Preparation of Fluvastatin Sodium Crystal Form XXXIX Example 111

In a 100 ml flask were placed Fluvastatin methyl ester (2.0 g) and asolution of NaOH (0.19 g) in EtOH (5 ml). The mixture was stirred atreflux for 3.5 h and propan-2-ol (40 ml) was added. The slurry wascooled to room temperature and stirred over night. The product wasisolated by filtration under nitrogen, washed with propan-2-ol (20 ml)and dried at 50EC in a vacuum oven for 24 h to obtain 1.93 g (95%) offluvastatin sodium crystal Form XXXIX.

36) Preparation of Fluvastatin Sodium Crystal Form XLI Example 112

Fluvastatin sodium Form XV (6.0 g) was dissolved in water (16 ml) atreflux temperature. Acetonitrile (60 ml) was added dropwise and themixture was stirred at reflux temperature for 1 h. Then, the mixture wascooled to room temperature and stirred at this temperature for 16 h.Another portion of acetonitrile (70 ml) was added to obtainprecipitation. After 3.5 h, the product was isolated by filtration undernitrogen, washed with acetonitrile (2×20 ml) and dried at 50EC in avacuum oven for 25 h to obtain 2.96 g (49%) of fluvastatin sodiumcrystal Form XLI.

37) Preparation of Fluvastatin Sodium Crystal Form XLII Example 113

Fluvastatin (3.0 g) was completely dissolved in MEK (40 ml) at roomtemperature. The solution was filtered to obtain a clear solution and97% NaOH (0.29 g) dissolved in MeOH (3 ml) was added to the solution.The solution was stirred at room temperature for 94 h to obtain agelatinous precipitate. The product was filtered under nitrogen flowwashed with MEK (2×11 ml) and dried at 50Ec is a vacuum oven for 25.5 hto obtain 2.6 (g) (85.5%) of fluvastatin sodium crystal Form XLII.

Example 114

Fluvastatin (2.0 g) was completely dissolved in MeOH (5 ml) at refluxtemperature and NaOH (s) (0.19 g) was added. The solution was stirred atreflux temperature for 3 h to obtain a precipitate having a paste-likeconsistency. ethyl acetate (40 ml) was added dropwise at refluxtemperature and then the solution was cooled to room temperature and theslurry was stirred for 3 h. The product was filtered under nitrogenflow, washed with ethyl acetate (2×10 ml) and dried at 50EC in a vacuumoven for 23 h to obtain 1.58 g (77.5%) of fluvastatin-sodium form XLII.

Example 115

Fluvastatin (3.0 g) was completely dissolved in dichloromethane (35 ml)at room temperature and the solution was filtered to obtain clearsolution. NaOH (s) (0.29 g) dissolved in MeOH (3 ml) was added to thesolution and the solution was then stirred at room temperature for 23 hto obtain a precipitate. The product was filtered under nitrogen flow,washed with dichloromethane (2×10 ml) and dried at 50° C. in a vacuumoven for 42 h to obtain 2.3 g (75%) of Fluvastatin-sodium form XLII.

Example 116

Fluvastatin-diol (3.0 g) was completely dissolved in dichloromethane (35ml) at room temperature and the solution was filtered to obtain clearsolution. NaOH (s) (0.29 g) dissolved in EtOH (5 ml) was added to thesolution and the solution was then stirred at room temperature for 23 hto obtain a precipitate. The product was filtered under nitrogen flow,washed with dichloromethane (2×10 ml) and dried at 50° C. in a vacuumoven for 42 h to obtain 1.88 g (61.5%) of fluvastatin-sodium form XLII.

38) Preparation of Fluvastatin Sodium Crystal Form XLIII Example 117

Fluvastatin sodium Form B (5.0 g) was dissolved in water (15 ml) atreflux temperature. Propan-2-ol (45 ml) was added dropwise and themixture was stirred at reflux temperature for 2 h. Then, the mixture wascooled to room temperature and stirred at this temperature for 16 h.Another portion of propan-2-ol (50 ml) was added to obtain a massiveprecipitation. After 7.5 h, the product was isolated by filtration undernitrogen, washed with propan-2-ol (2×25 ml) and dried at 50EC in avacuum oven for 24 h to obtain 0.74 g (15%) of fluvastatin sodium FormXLIII.

Example 118

Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.)in water. The mixture was stirred at about 70EC for 2 h until the rawmaterial wasn't observed by HPLC. After this time, propan-2-ol (10 ml)was dripped and the solution was cooled slowly to room temperature.Another 40 ml of propan-2-ol (in 3 portions) were added at roomtemperature to the solution but no precipitation was ECcurred. Thesolution was stirred overnight and a gel-like precipitate formed. Themixture was heated to reflux to dissolve the gel. The mixture was thenallowed to cool to room temperature. A yellow slurry was obtained. Afterstirring overnight, another 15 ml of propan-2-ol were added dropwise.The product was isolated by filtration under nitrogen, washed withpropan-2-ol (25 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 0.46 g (22.6%) of fluvastatin sodium Form XLIII.

39) Preparation of Fluvastatin Sodium Crystal Form XLIV Example 119

Amorphous fluvastatin sodium (1.5 g) was suspended in propan-2-ol (31ml) at reflux temperature for 4.25 h. Then, the suspension was cooled toroom temperature and stirred at this temperature for 1 h. The productwas filtered under nitrogen flow, washed with propan-2-ol (2×35 ml) anddried at 50EC in a vacuum oven for 23 h to obtain 0.4 g (25%) offluvastatin sodium Form XLIV.

Example 120

Fluvastatin methyl ester (3.0 g) was added to acetone (30 ml) and thesolution was stirred at room temperature. NaOH (1 eq.) in EtOH (3 ml)was added to the solution. The mixture was stirred overnight. Theproduct that precipitated was isolated by filtration under nitrogen,washed with acetone (100 ml) and dried at 50EC in a vacuum oven for 24 hto obtain 2.45 g (80.8%) of fluvastatin sodium Form XLIV.

40) Preparation of Fluvastatin Sodium Crystal Form XLV Example 121

A suspension of fluvastatin sodium Form Am1 (2.6 g) in propan-2-ol (36ml) was stirred at room temperature for 25 h. The product was thenfiltered under nitrogen flow, washed with propan-2-ol (2×20 ml) anddried at 50EC in a vacuum oven for 20.5 h to obtain 2.4 g (92%) offluvastatin sodium crystal Form XLV.

Preparation of Form Am1

Fluvastatin-diol-methyl ester (FDME) (3.0 g) was added to cyclohexane(60 ml) and the mixture was heated to reflux. NaOH (1 eq.) dissolved inMeOH (3 ml) was added to the slurry solution which became clear. After15 min precipitant was appeared. After another hour the mixture wascooled to rt, cyclohexane (40 ml) was added and it was stirredovernight. The product was isolated by filtration under nitrogen, washedwith cyclohexane (90 ml) and dried at 50*C in a vacuum over for 24 hoursto obtain 2.73 gr (90%) of Fluvastatin sodium Am1.

41) Preparation of Fluvastatin Sodium Crystal Form XLVI Example 122

In a 100 ml flask were placed fluvastatin methyl ester (2.42 g), EtOH (5ml) and a solution of NaOH (0.23 g) in EtOH (7 ml). The mixture wasstirred at reflux for 2.5 h and acetonitrile (50 ml) was added. Theslurry was stirred at reflux for another 3 h then cooled to roomtemperature and stirred over night. The product was isolated byfiltration under nitrogen and dried at 50EC in a vacuum oven for 24 h toobtain 2.02 g (83%) of fluvastatin sodium crystal Form XLVI.

42) Preparation of Fluvastatin Sodium Crystal Form XLVII Example 123

About 300 mg fluvastatin sodium Form XVIII was placed on flat disheswith a diameter of 35 mm and introduced in a chamber with controlledrelative humidity of about 80% for 25 days, and fluvastatin sodium formXLVII was recovered.

43) Preparation of Fluvastatin Sodium Crystal Form XLVIII Example 124

To a three necked flask was added fluvastatin methyl ester (3.0 g) andNaOH (1 eq.) dissolved in MeOH (7.5 ml). The mixture refluxed for 6.5 h.Then, acetonitrile (50 ml) was added dropwise to the refluxing solutionover 10 min. The mixture was then cooled to room temperature and stirredfor 46 h. The product was isolated by filtration under nitrogen, washedwith acetonitrile (50 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 1.84 g (60.7%) of fluvastatin sodium Form XLVIII.

Example 125

Fluvastatin sodium Form B (5.0 g) was stirred in MeOH (40 ml) at refluxfor 5 h. The slurry was cooled to room temperature and stirred at roomtemperature for 17 h. The product was filtered under nitrogen flow,washed with MeOH (2×20 ml) and dried at 50° C. in a vacuum oven for 21.5h to obtain 0.28 g (5.6%) of fluvastatin sodium Form XLVIII.

Example 126

Fluvastatin sodium Form B (5.0 g) was dissolved in MeOH (24 ml) at roomtemperature. The solution was heated to reflux temperature to obtain aprecipitate. The slurry formed was cooled to room temperature andstirred at room temperature for 19.5 h. The product was filtered undernitrogen flow, and dried at 50° C. in a vacuum oven for 24 h to obtain0.53 g (10.6%) of fluvastatin sodium Form XLVIII.

Example 127

Fluvastatin (3 g) was completely dissolved in MeOH (15 ml) at refluxtemperature. Then, the solution was filtered to obtain a clear solutionand heated to reflux again. NaOH (s) (0.29 g) was added at refluxtemperature to obtain a precipitate. The slurry was cooled to roomtemperature to obtain a paste-like mixture. Acetone (30 g) was addeddropwise at room temperature and the solution stirred at roomtemperature for 21 h to obtain a massive precipitate. The product wasfiltered under nitrogen flow, washed with acetone (2×15 ml) and dried at50° C. in a vacuum oven for 22.5 h to obtain 1.89 g (62%) of fluvastatinsodium Form XLVIII.

44) Preparation of Fluvastatin Sodium Crystal Form XLIX Example 128

Fluvastatin sodium crystal Form B (5.0 g) was dissolved in methanol (40ml) at room temperature. The solution was heated to reflux temperatureand MTBE (100 ml) was added dropwise to obtain a precipitate. Theobtained suspension was stirred at reflux temperature for 1 h. Then, themixture was cooled to room temperature and stirred at this temperaturefor 16 h. The product was filtered under nitrogen flow, washed with MTBE(2×10 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 3.2 g(64%) of fluvastatin sodium crystal Form XLIX.

45) Preparation of Fluvastatin Sodium Crystal Form L Example 129

Fluvastatin sodium (5.0 g) was dissolved in methanol (35 ml) at roomtemperature. The solution was heated to reflux temperature and ethylacetate (100 ml) was added dropwise. A precipitation was obtained duringaddition of ethyl acetate. The mixture was stirred at reflux temperaturefor 1.5 h. Then, the suspension was cooled to room temperature andstirred at this temperature for 16 h. The product was filtered undernitrogen flow and dried at 50EC in a vacuum oven for 24 h to obtain 0.7g (14%) of Fluvastatin sodium Form L.

46) Preparation of Fluvastatin Sodium Crystal Form LI Example 130

Fluvastatin sodium crystal Form B (5.0 g) was dissolved in methanol (50ml) at room temperature. The solution was heated to reflux temperatureand acetonitrile (100 ml) was added dropwise to obtain a precipitate.The obtained suspension was stirred at reflux temperature for 1 h. Then,the mixture was cooled to room temperature and stirred at thistemperature for 16 h. The product was filtered under nitrogen flow,washed with acetonitrile (2×15 ml) and dried at 50EC in a vacuum ovenfor 23 h to obtain 0.73 g (15%) of fluvastatin sodium crystal Form LI.

47) Preparation of Fluvastatin Sodium Crystal Form LIII Example 131

Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol(112 ml) at room temperature. The solution was heated to refluxtemperature and ethyl acetate (320 ml) was added dropwise to obtain aprecipitate. The obtained suspension was stirred at reflux temperaturefor 1.5 h. Then, the mixture was cooled to room temperature and stirredat this temperature for 16 h. The product was filtered under nitrogenflow, washed with ethyl acetate (1×25 ml) and dried at 50EC in a vacuumoven for 23.5 h to obtain 2.1 g. (13%) of fluvastatin sodium crystalForm LIII.

48) Preparation of Fluvastatin Sodium Crystal Form LIV Example 132

Fluvastatin (3.52 g) was stirred in a solution of H₂O (9.9 ml) and NaOH(s) (0.32 g) at room temperature to obtain a mud-like suspension. Thesuspension was stirred at room temperature over night. The product wasfiltered under nitrogen flow, washed with H₂O (2×3 ml) and dried at 50°C. in a vacuum oven for 24 h to obtain 3.36 g (65.8%) of fluvastatinsodium Form LIV.

49) Preparation of Fluvastatin Sodium Crystal Form LV Example 133

Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) anddissolved by heating the mixture to reflux. The solution was then cooledto about 40EC and NaOH (1 eq.) dissolved in MeOH (7.5 ml) was added.Turbidity appeared immediately. After 30 minutes an oil residueseparated from the mixture. The mixture was heated again to about 55ECfor 3 h to dissolve the oil. The product was isolated by filtrationunder nitrogen, washed with acetonitrile (40 ml) and dried at 50EC in avacuum oven for 24 h to obtain 2.48 g (81.1%) of fluvastatin sodium FormLV.

50) Preparation of Fluvastatin Sodium Crystal Form LVI Example 134

In a 250 ml flask were placed Fluvastatin-acetonide-methylester (4.4 g),THF (44 ml) and 1.5% HCl solution (0.67 ml). The mixture was stirred atroom temperature for 10 h, then NaOH (0.25 g) was added and the solventswere evaporated. The residue was dissolved in acetone (80 ml), NaOH(0.43 g) was added and the mixture was stirred at room temperature overnight. The product was isolated by filtration under nitrogen, washedwith acetone (50 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 1.37 g of fluvastatin sodium crystal Form LVI.

51) Preparation of Fluvastatin Sodium Crystal Form LVII Example 135

Fluvastatin sodium Form VII (20.5 g) was suspended in absolute ethanol(246 ml) at room temperature for 21 h. The product was then filteredunder nitrogen flow, washed with absolute ethanol (2×40 ml) and dried at50EC in a vacuum oven for 24 h to obtain 11.8 g (58%) of fluvastatinsodium Form LVII.

52) Preparation of Fluvastatin-Sodium Crystal Form LVIII Example 136

Propan-2-ol (120 ml) was heated to reflux temperature. Fluvastatinsodium (5.0 g) was added to the boiled solvent. The mixture was stirredat reflux temperature for 3 h. Then, the suspension was cooled to roomtemperature and stirred at this temperature for 16 h. The product wasfiltered under nitrogen flow, washed with propan-2-ol (2×25 ml) anddried at 50EC in a vacuum oven for 22 h to obtain 4.7 g (95%) offluvastatin sodium Form LVIII.

53) Preparation of Fluvastatin-Sodium Crystal Form LX Example 137

Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol(112 ml) at room temperature. The solution was heated to refluxtemperature and ethyl acetate (320 ml) was added dropwise to obtain aprecipitate. The obtained suspension was stirred at reflux temperaturefor 1.5 h. Then, the mixture was cooled to room temperature and stirredat this temperature for 16 h. The product was filtered under nitrogenflow, washed with ethyl acetate (1×20 ml) and dried at 50EC in a vacuumoven for 24 h to obtain 2.3 g (14%) of fluvastatin sodium crystal FormLX.

54) Preparation of Fluvastatin-Sodium Crystal Form LXIV Example 138

In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and MeOH(30 ml). The mixture was heated to reflux for dissolution and NaOH(0.42) was added in two portions. Precipitant was appeared at refluxtemperature and wasn't dissolved after addition of another 45 ml of MeOHduring 4 h. The slurry mixture was cooled to room temperature andstirred over night. The precipitant was dissolved, acetone (150 ml) wasadded and the mixture was stirred at room temperature for 22 h. Theproduct was isolated by filtration under nitrogen, washed with acetone(35 ml) and dried at 50EC in a vacuum oven for 22.5 h to obtain 1.68 gof fluvastatin sodium crystal Form LXIV.

Example 139

Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) andfiltered. A solution of NaOH (1.46 g) in MeOH (15 ml) was added and thesolution was stirred at room temperature. After 2 h a solution of NaOH(0.73 g) in MeOH (15 ml) was added and the mixture was stirred overnight. The product was isolated by filtration under nitrogen, washedwith acetone and dried at 50EC in a vacuum oven for 24 h to obtainfluvastatin sodium form LXIV.

Example 140

Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) andfiltered. A solution of NaOH (1.46 g) in MeOH (15 ml) was added and thesolution was stirred at room temperature. After 2 h a solution of NaOH(0.73 g) in MeOH (15 ml) was added. After 2 h the mixture was cooled to14EC and stirred at this temperature over night. The product wasisolated by filtration under nitrogen, washed with acetone and dried at50EC in a vacuum oven for 24 h to obtain fluvastatin sodium form LXIV.

55) Preparation of Fluvastatin-Sodium Crystal Form LXV Example 141

In a 100 ml flask were placed Fluvastatin methyl ester (3.0 g), MeOH (20ml) and NaOH (0.29 g). After a clear solution was obtained propan-2-ol(80 ml) was added and the solution was stirred at room temperature overnight. A little precipitation occurred, propan-2-ol (40 ml) was addedand the solution was stirred at room temperature for another night. Theproduct was isolated by filtration under nitrogen, washed with acetone(35 ml) and dried at 50EC in a vacuum oven for 22.5 h to obtain 0.92 gof fluvastatin sodium crystal Form LXV.

Example 142

Fluvastatin methyl ester (3.0 g) was dissolved in MeOH (15 ml) byheating to reflux. NaOH (0.29 g) was added and the clear solution wasstirred at reflux for 30 min, then acetone (75 ml) was added. Thesolution was cooled to room temperature and stirred over night. Theproduct was isolated by filtration under nitrogen, washed with acetone(35 ml) and dried at 50EC in a vacuum oven for 21.5 h to obtain 1.34 gof fluvastatin sodium crystal Form LXV.

56) Preparation of Fluvastatin-Sodium Crystal Form LXVI Example 143

In a 50 ml flask were placed fluvastatin sodium crystal Form VI (1.98 g)and water (4 ml), then the mixture was heated to reflux for dissolution.After 2 h the solution was cooled to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washedwith water (3 ml) and dried at 50EC in a vacuum oven for 24 h to obtain1.25 g (63%) of fluvastatin sodium crystal Form LXVI.

Example 144

Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (10 ml)at reflux temperature. The solution was stirred at reflux temperaturefor 2 h. Then, the solution was cooled to room temperature and stirredat this temperature for 16 h to obtain a precipitate. The product wasfiltered under nitrogen flow, washed with water (2×2 ml) and dried at50EC in a vacuum oven for 24.5 h to obtain 4.4 g (89%) of fluvastatinsodium crystal Form LXVI.

Example 145

Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (14ml) at reflux temperature. The solution was stirred at refluxtemperature for 1.25 h. Then, the solution was cooled to roomtemperature and stirred at this temperature for 16 h to obtain aprecipitate. The product was filtered under nitrogen flow, washed withwater (×3 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 4.2g (84%) of fluvastatin sodium crystal Form LXVI.

57) Preparation of Fluvastatin-Sodium Crystal Form LXVII Example 146

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and asolution of NaOH (0.36 g) in MeOH (5 ml) was added. After 3 h NaOH(0.072 g) was added and the mixture was stirred at room temperature foranother 21 h. NaOH (0.073 g) was added and the mixture was stirred foranother 4 h. The product was isolated by filtration under nitrogen,washed with acetone (55 ml) and dried at 50EC in a vacuum oven for 24 hto obtain 2.64 g of fluvastatin sodium crystal Form LXVII.

Example 147

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), asolution of NaOH (0.58 g) in MeOH (8 ml) was added and the mixture wasstirred at room temperature for another 3.75 h. The product was isolatedby filtration under nitrogen, washed with acetone (40 ml) and dried at50EC in a vacuum oven for 21 h to obtain 2.54 g of fluvastatin sodiumcrystal Form LXVII.

Example 148

Fluvastatin methyl ester (10.0 g) was dissolved in acetone (150 ml) anda solution of NaOH (0.94 g) in MeOH (10 ml) was added. After 26.5 h,NaOH (0.47 g) was added and the mixture was stirred at room temperatureover night. The product was isolated by filtration under nitrogen,washed with acetone (20 ml) and dried at 50EC in a vacuum oven for 23 hto obtain 8.01 g of fluvastatin sodium crystal Form LXVII.

58) Preparation of Fluvastatin-Sodium Crystal Form LVIII Example 149

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and asolution of NaOH (0.44 g) in MeOH (6 ml) was added. After 29 h, NaOH(0.14 g) was added and the mixture was stirred at room temperature foranother 1 h, then it was cooled with ice bath for 30 min. The productwas isolated by filtration under nitrogen, washed with acetone (38 ml)and dried at 50EC in a vacuum oven for 22 h to obtain 2.76 g offluvastatin sodium crystal Form LXVIII.

Example 150

Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) andfiltered. A solution of NaOH (1.46 g) in MeOH (15 ml) was added and thesolution was stirred at room temperature. After 27 h, a solution of NaOH(0.73 g) in MeOH (15 ml) was added and the mixture was stirred overnight. The product was isolated by filtration under nitrogen, washedwith acetone and dried at 50EC in a vacuum oven for 24 h to obtainfluvastatin sodium form LXVIII.

59) Preparation of Fluvastatin Sodium Crystal Form LXIX Example 151

In a 50 ml flask were placed fluvastatin sodium crystal Form VI (1.63 g)and propan-2-ol (28 ml) then the mixture was heated to reflux. After 2h, propan-2-ol (4 ml) was added, the slurry was stirred at reflux foranother 20 min, cooled to room temperature and stirred over night. Theproduct was isolated by filtration under nitrogen, washed withpropan-2-ol (30 ml) and dried at 50EC in a vacuum oven for 24 h toobtain 1.52 g (93%) of fluvastatin sodium crystal Form LXIX.

60) Preparation of Fluvastatin Sodium Crystal Form LXX Example 152

In a 100 ml flask were placed fluvastatin sodium crystal Form LXVII (2.0g) and water (3.4 ml). The mixture was heated to reflux for dissolvingand acetone (34 ml) was added. After 2 h, the mixture was cooled to roomtemperature and stirred over night. The product was isolated byfiltration under nitrogen, washed with acetone (20 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.69 g (84.5%) of fluvastatinsodium crystal Form LXX.

61) Preparation of Fluvastatin Sodium Crystal Form LXXI Example 153

In a 100 ml flask were placed fluvastatin sodium crystal Form LXVII (2.0g) and water (2 ml). The mixture was heated to reflux and acetone (74ml) was added. After 2 h, the mixture was cooled to room temperature andstirred over night. The product was isolated by filtration undernitrogen, washed with acetone (20 ml) and dried at 50EC in a vacuum ovenfor 24 h to obtain 1.85 g (92.5%) of fluvastatin sodium crystal FormLXXI.

62) Preparation of Fluvastatin Sodium Crystal Form LXXII Example 154

In a 100 ml flask were placed fluvastatin sodium crystal Form VI (1.33g), acetone (28 ml) and water (0.7 ml). The mixture was heated to refluxfor 2 h, then cooled to room temperature and stirred over night. Theproduct was isolated by filtration under nitrogen, washed with acetone(20 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.26 g(95%) of fluvastatin sodium crystal Form LXXII.

Example 155

In a 100 ml flask were placed fluvastatin sodium crystal Form VI (1.12g) and acetonitrile (19 ml). The mixture was heated to reflux for 2 h,then cooled to room temperature and stirred over night. The product wasisolated by filtration under nitrogen, washed with acetonitrile (20 ml)and dried at 50EC in a vacuum oven for 24 h to obtain 1.02 g (86%) offluvastatin sodium crystal Form LXXII.

63) Preparation of Fluvastatin Sodium Crystal Form LXXIV Example 156

A suspension of fluvastatin sodium crystal Form B (30.0 g) in a mixtureof propan-2-ol (501 ml) and water (51 ml) was heated to refluxtemperature for 16 h. The suspension was then cooled to roomtemperature. The product was filtered under nitrogen flow, washed withpropan-2-ol (2×25 ml) and dried at 50EC in a vacuum oven for 21.5 h toobtain 4.7 g (16%) of fluvastatin sodium crystal Form LXXIV.

Example 157

A suspension of fluvastatin sodium crystal Form B (2.0 g) in a mixtureof propan-2-ol (33.3 ml) and water (4.3 ml) was heated to refluxtemperature for 4 h. The suspension was then cooled in an ice-bath. Theproduct was filtered under nitrogen flow, washed with propan-2-ol (2×10ml) and dried at 50EC in a vacuum oven for 17.5 h to obtain 0.4 g (20%)of fluvastatin sodium crystal Form LXXIV.

64) Preparation of Fluvastatin Sodium Crystal Form LXXV Example 158

Fluvastatin sodium crystal Form XXX (2.0 g) was refluxed in MeOH (10 ml)for 15 h, cooled to room temperature and stirred for another 2 h. Theproduct was isolated by filtration under nitrogen, washed with MeOH (15ml) and dried at 50EC in a vacuum oven for 24 h to obtain 0.48 g (24%)of fluvastatin sodium crystal Form LXXV.

65) Preparation of Fluvastatin Sodium Crystal Form LXXVI Example 159

A 250 round bottom flask was loaded with fluvastatin methyl ester (12.0g), EtOH (60 ml), water (36 ml) and NaOH (1 eq.). After 2 h the ethanolwas evaporated and the residue was divided to 4 fractions. Water wasadded (completing to 20 vol) and extracted twice with ethyl acetate. Theproduct was isolated by distillation of water to obtain wet fluvastatinsodium crystal Form LXXVI. (the sample was kept at room temperature for3 days).

66) Preparation of Fluvastatin Sodium Crystal Form LXXVII Example 160

Fluvastatin methyl ester (3.0 g) was dissolved in ethyl acetate (90 ml),a solution of NaOH (0.2 g) in water (1 ml) was added and the mixture wasstirred at room temperature over night. The product was isolated byfiltration under nitrogen, washed with ethyl acetate (50 ml) and driedat 50EC in a vacuum oven for 24 h to obtain 1.52 g (49.7%) offluvastatin sodium crystal Form LXXVII.

67) Preparation of Fluvastatin Sodium Crystal Form LXXVIII Example 161

A 100 ml round bottom flask was loaded with fluvastatin methyl ester(4.0 g, 9.4 mmole), water (32 ml) and NaOH (0.39 g). The mixture wasstirred for 3 days at room temperature then extracted with ethyl acetate(32 ml, 16 ml). The aqueous solution was evaporated, propan-2-ol (40 ml)was added and the mixture was stirred at room temperature over night.Precipitation occurred after scraping the mixture with spatula andstirring for another day. The product was isolated by filtration undernitrogen flow, washed with propan-2-ol (20 ml) and dried at 50EC in avacuum oven for 24 h to obtain 1.28 g (31%) of fluvastatin sodiumcrystal Form LXXVIII.

Example 162

A 100 ml round bottom flask was loaded with Fluvastatin methyl ester(3.0 g, 7.08 mmole), water (30 ml) and NaOH (0.29 g). The mixture wasstirred for 3 h at room temperature then extracted with ethyl acetate(30 ml). The aqueous solution was evaporated, acetonitrile (12 ml) wasadded and the mixture was stirred at room temperature over night. Theproduct was isolated by filtration under nitrogen flow, washed withacetonitrile (20 ml) and dried at 40EC in a vacuum oven for 24 h toobtain 0.37 g (12%) of fluvastatin sodium crystal Form LXXVIII.

68) Preparation of Fluvastatin Sodium Form XC Example 163

Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (140ml). The obtained solution was filtered and cyclohexane (2×140 ml) wasadded in two portions. The mixture was stirred at room temperature for26 h to obtain a massive precipitate. Then, the product was filtered,washed with cyclohexane (2×25 ml) and dried at 50EC in a vacuum oven for21.5 h to obtain 1.7 g (55%) of fluvastatin sodium Form XC.

69) Preparation of Fluvastatin Sodium Form XCI Example 164

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in ethylacetate (75 ml) was stirred at reflux temperature for 16 h. Then, thesuspension was cooled to room temperature. The product was filteredunder nitrogen flow, washed with ethyl acetate (4×25 ml) and dried at50EC in a vacuum oven for 21 h to obtain 3.9 g (78%) of fluvastatinsodium Form XCI.

70) Preparation of Fluvastatin Sodium Form XCII Example 165

Fluvastatin sodium crystal Form B (1.0 g) was dissolved in ethanol (10ml) and methanol (1 ml) at reflux temperature. Hexanes (10 ml) wereadded in one portion and the turbid solution was stirred at refluxtemperature for 4 h. A precipitation was obtained during this time.Then, the suspension was cooled to room temperature and stirred at thistemperature for 16 h. The product was filtered under nitrogen flow,washed with hexanes (3×7 ml) and dried at 50EC in a vacuum oven for 19 hto obtain 0.67 g (67%) of fluvastatin sodium Form XCII.

71) Preparation of Fluvastatin Sodium Form XCIII Example 166

A suspension of fluvastatin sodium crystal Form XV (5.0 g) inpropan-1-ol (50 ml) was stirred at room temperature for 25 h. Theproduct was then filtered under nitrogen flow, washed with propan-1-ol(3×40 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 3.8 g(76%) of fluvastatin sodium Form XCIII.

72) Preparation of Fluvastatin Sodium Form XCIV Example 167

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in butan-1-ol(50 ml) was stirred at room temperature for 24 h. The product was thenfiltered under nitrogen flow, washed with butan-1-ol (2×20 ml) and driedat 50EC in a vacuum oven for 24 h to obtain 6.0 g (120%) of fluvastatinsodium Form XCIV.

73) Preparation of Fluvastatin Sodium Form XCV Example 168

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in ethylacetate (90 ml) was stirred at room temperature for 19 h. The productwas then filtered under nitrogen flow, washed with ethyl acetate (2×20ml) and dried at 50EC in a vacuum oven for 22 h to obtain 5.2 g (104%)of fluvastatin sodium Form XCV.

Example 169

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in acetone(70 ml) was stirred at room temperature for 23 h. The product was thenfiltered under nitrogen flow, washed with acetone (2×15 ml) and dried at50EC in a vacuum oven for 20 h to obtain 4.6 g (92%) of fluvastatinsodium Form XCV.

Example 170

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in1,4-dioxane (50 ml) was stirred at room temperature for 24 h. Theproduct was then filtered under nitrogen flow, washed with 1,4-dioxane(2×30 ml) and dried at 50EC in a vacuum oven for 23 h to obtain 4.4 g(88%) of fluvastatin sodium Form XCV.

Example 171

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in MEK (70ml) was stirred at room temperature for 30 h. The product was thenfiltered under nitrogen flow, washed with MEK (2×20 ml) and dried at50EC in a vacuum oven for 21 h to obtain 4.7 g (93%) of fluvastatinsodium Form XCV.

74) Preparation of Fluvastatin Sodium Form XCVI Example 172

A suspension of fluvastatin sodium crystal Form XV (5.0 g) in THF (70ml) was stirred at room temperature for 29 h. Then, the product wasfiltered under nitrogen flow, washed with THF (2×20 ml) and dried at50EC in a vacuum oven for 20 h to obtain 4.1 g (82%) of fluvastatinsodium Form XCVI.

75) Preparation of Fluvastatin Sodium Form XCVII Example 173

In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) andcyclohexane (60 ml) then the mixture was heated to reflux. A solution ofNaOH (0.29 g) in MeOH (3 ml) was added and the mixture was stirred atreflux for 1.6 h. The slurry was cooled to room temperature, cyclohexane(40 ml) was added and the mixture was stirred over night. The productwas isolated by filtration under nitrogen, washed with cyclohexane (90ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.81 g (93%)of fluvastatin sodium Form XCVII.

76) Preparation of Fluvastatin Sodium Form XCVIII Example 174

Fluvastatin methyl ester (3.0 g) was dissolved in a solution of NaOH(0.29 g) in MeOH (7.5 ml) by heating to reflux. The clear solution wasstirred at reflux for 85 min and acetonitrile (50 ml) was added. Thesolution was cooled to room temperature and stirred over night. Theproduct was isolated by filtration under nitrogen, washed withacetonitrile (50 ml) and dried at 50EC in a vacuum oven for 25.5 h toobtain 0.97 g of fluvastatin sodium Form XCVIII.

77) Preparation of Fluvastatin Sodium Form XCIX Example 175

In a 50 ml flask were placed fluvastatin sodium crystal Form VI (1.02 g)and EtOH (10 ml). After 2.5 h EtOH (15 ml) was added and the mixture wasstirred at room temperature over night. The product was isolated byfiltration under nitrogen, washed with EtOH (20 ml) and dried at 50EC ina vacuum oven for 24 h to obtain 0.14 g (14%) of fluvastatin sodium FormXCIX.

78) Preparation of Fluvastatin Sodium Form C Example 176

Fluvastatin methyl ester (3.0 g) was dissolved in dichloromethane (35ml). NaOH (0.29 g) was added and the mixture was stirred at room overnight. The product was isolated by filtration under nitrogen, washedwith dichloromethane (20 ml) and dried at 50EC in a vacuum oven for 24 hto obtain 1.89 g (62%) of fluvastatin sodium Form C.

79) Preparation of Fluvastatin Sodium Form CI Example 177

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), asolution of NaOH (0.58 g) in MeOH (8 ml) was added and the mixture wasstirred at room temperature for another 3.5 h. The product was isolatedby filtration under nitrogen, washed with acetone (40 ml) and dried at50EC in a vacuum oven for 22.5 h to obtain 2.37 g of fluvastatin sodiumForm CI.

Example 178

Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml) and asolution of NaOH (0.75 g) in MeOH (8 ml) was added. The mixture washeated to 50EC for 4.25 h, cooled to room temperature and stirred overnight. NaOH (0.2 g) was added and the mixture was heated again to 50EC.After 5.5 h a solution of NaOH (0.2 g) in MeOH (8 ml) was added andstirred for 1.5 h, then the mixture was cooled to room temperature andstirred for 1 h. The product was isolated by filtration under nitrogen,washed with acetone (100 ml) and dried at 50EC in a vacuum oven for 21.5h to obtain 7.26 g of fluvastatin sodium Form CI.

80) Preparation of Fluvastatin Sodium Form CII Example 179

Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml),filtered and cooled to 10EC. A solution of NaOH (0.75 g) in MeOH (8 ml)was added and the mixture was stirred at 10EC for 10 h. A solution ofNaOH (0.4 g) in MeOH (4 ml) was added to the mixture in 3 portionsduring this time. The product was isolated by filtration under nitrogen,washed with acetone (120 ml) and dried at 50EC in a vacuum oven for 22.5h to obtain 5.04 g of fluvastatin sodium Form CII.

81) Preparation of Fluvastatin Sodium Form CIII Example 180

Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) andfiltered. A solution of NaOH (0.29 g) in water (1 ml) was added and themixture was stirred at room temperature over night. The product wasisolated by filtration under nitrogen, washed with acetone (40 ml) anddried at 50EC in a vacuum oven for 25.5 h to obtain 1.08 g offluvastatin sodium Form CIII.

82) Preparation of Fluvastatin Sodium Form CIV Example 181

Fluvastatin methyl ester (3.0 g) was dissolved in THF (30 ml) and theNaOH (1 eq.) was added. After 2.5 h hexanes (60 ml) was added and theslurry stirred at room temperature over night. The product was isolatedby filtration under nitrogen, washed with hexanes (30 ml) and dried at50EC in a vacuum oven for 24 h to obtain 1.2 g (39%) of fluvastatinsodium Form CIV.

83) Preparation of Fluvastatin Sodium Form CV Example 182

Fluvastatin methyl ester (5.0 g) was dissolved in acetonitrile (100 ml)by heating. At 50EC a solution of NaOH (1 eq.) in water (1.25 ml) wasadded and the mixture was stirred at this temperature for 2 h, thencooled to room temperature and stirred over night. The product wasisolated by filtration under nitrogen, washed with acetonitrile (30 ml)and dried at 50EC in a vacuum oven for 24 h to obtain 1.75 g (34.5%) offluvastatin sodium Form CV.

84) Preparation of Fluvastatin Sodium Crystal Form B Example 183

Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.)in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred atreflux temperature for 2 h. After this time the raw material was notobserved by HPLC. MTBE (58 ml) was dripped into the solution over 2 h.The solution was cooled slowly to room temperature and was stirredovernight. The product was isolated by filtration under nitrogen, washedwith MTBE (50 ml) and dried at 50EC in a vacuum oven for 24 h to obtain2.78 g (91.3%) of fluvastatin sodium Form B.

85) Preparation of Amorphous Fluvastatin Sodium Example 184

Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (40 ml) at 85EC.Then, the solution was cooled to room temperature and stirred at thistemperature for 70 h. The product was filtered under nitrogen flow anddried at 50EC in a vacuum oven for 25 h to obtain 2.7 g (90%) ofamorphous fluvastatin sodium.

Example 185

Fluvastatin methyl ester (3.0 g) was added to cyclohexane (60 ml) andthe slurry was heated to reflux. A solution of NaOH (1 eq.) in MeOH (3ml) was added to the slurry solution which became clear. After 15 min. aprecipitate formed. After another hour, the mixture was cooled to roomtemperature and cyclohexane (40 ml) was added. The mixture was stirredover night. The product was isolated by filtration under nitrogen,washed with cyclohexane (90 ml) and dried at 50EC in a vacuum oven for24 h to yield 2.73 g (90%) of amorphous fluvastatin sodium.

Example 186

A suspension of amorphous fluvastatin (5.0 g) in propan-2-ol (104 ml)was stirred at reflux temperature for 4.5 h. Then, the suspension wascooled to room temperature and stirred at this temperature for 16 h. Theproduct was filtered under nitrogen flow, washed with propan-2-ol (2×10ml) and dried at 50EC in a vacuum oven for 24 h to obtain 3.8 g (76%) ofamorphous fluvastatin sodium.

Example 187

A 100 ml round bottom flask was loaded with Fluvastatin -diol-t-butylester (20.0 g, 43 mmole), MeOH (120 ml) and NaOH (1.82 gr) in water (10ml). The mixture was heated to 35° C. The solution became clear andwater (50 ml) was added. The mixture was stirred for 3 hr then the MeOHwas evaporated. The volume of the water was completed to 8 vol. and themixture was extracted with MTBE (120 ml). The organic solvents residuewas evaporated and solution was divided to two portions of 68 ml. NaCl(0.7 gr) was added to one of the solutions and it was cooled to 4° C.during 1 hr. The product was isolated after 1 hr by filtration undernitrogen and dried at 40° C. in a vacuum oven for 24 hours to obtain6.04 gr (65%) of Fluvastatin sodium crystal form D.

Example 188

Fluvastatin-diol-methyl ester (FDME) (4.0 g) was dissolved in acetone(40 ml). A solution of NaOH (0.38 gr) in MeOH (4 ml) was added and themixture was stirred at room temperature for 20 hr. The product wasisolated by filtration under nitrogen, washed with acetone (20 ml) anddried at 50° C. in a vacuum oven for 26 hours to obtain 3.35 gr (82.2%)of Fluvastatin sodium crystal form VI.

Example 189

Fluvastatin-diol-methyl ester (FDME) (3.5 g) was dissolved in acetone(35 ml). A solution of NaOH (0.34 gr) in MeOH (4 ml) was added and themixture was stirred at room temperature for 22.5 hr. The product wasisolated by filtration under nitrogen, washed with acetone (20 ml×2) anddried at 50° C. in a vacuum oven for 26 hours to obtain 3.22 gr (90.3%)of Fluvastatin sodium crystal form VI.

1. Fluvastatin sodium (Form LXVI) having an PXRD pattern withcharacteristic peaks at 3.6, 10.8, 17.8, 18.3 and 21.6±0.2 degreestwo-theta
 2. The fluvastatin sodium of claim 1, further characterized bypeaks at 7.2, 12.2, 14.4 and 25.5±0.2 degrees two-theta.
 3. Thefluvastatin sodium of claim 1, further characterized by an XRD patternas depicted in FIG.
 81. 4. A process for preparing crystallinefluvastatin of claim 1 comprising heating a solution of fluvastatinsodium in water and cooling the solution to precipitate the crystallineform.